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New avenues for the treatment of huntington’s disease.

1. Introduction

1.1. mechanisms of neurodegeneration in hd, 1.1.1. excitotoxicity, 1.1.2. dopaminergic dysfunction, 1.1.3. mitochondrial dysfunction and oxidative stress, 1.1.4. autophagy dysregulation, 1.1.5. decreased trophic support, 1.2. animal models of hd, 1.2.1. transgenic truncated hd mouse models, 1.2.2. transgenic full-length hd mouse models, 1.2.3. knock-in hd mouse models, 2. currently available treatments for hd, 2.1. treatments to manage motor symptoms, 2.1.1. hyperkinesia, dopamine modulators, dopamine antagonists, anti-glutamatergic drugs, 2.1.2. hypokinesia and rigidity, 2.2. treatments to manage non-motor symptoms, 2.2.1. treatment of cognitive impairment, 2.2.2. depression, 2.2.3. other behavioral symptoms, 3. clinical trials, 3.1. dopaminergic modulation, 3.2. glutamatergic modulation, 3.3. synaptic modulation, 3.4. modulation of bdnf levels, 3.5. mitochondrial function and biogenesis, 3.6. aggregate inhibition, 3.7. antibody therapy, 3.8. genetic manipulations, 3.9. dietary supplementation, 3.10. combined pharmacological therapies, 3.11. stem cell therapies, 3.12. deep brain stimulation (dbs), 3.13. physical activity, 4. pre-clinical experimental therapeutic approaches, 4.1. neurotrophic factors, 4.1.1. brain-derived neurotropic factor (bdnf), 4.1.2. glial cell line-derived neurotropic factor (gdnf), 4.1.3. other neurotrophic factors, 4.2. autophagy regulators, 4.2.1. direct up-regulation of autophagy modulators, 4.2.2. pharmacologic modulation of autophagy, 4.3. epigenetic modulators, 4.3.1. sirtuins, 4.3.2. histone deacetylase (hdac) inhibitors and lysine deacetylase (kdac) inhibitors, 4.4. nanotechnology and nanoparticles, 4.5. stem cell treatment, 4.6. genetic manipulations, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

• Brinkman, R.R.; Mezei, M.M.; Theilmann, J.; Almqvist, E.; Hayden, M.R. The likelihood of being affected with huntington disease by a particular age, for a specific CAG size. Am. J. Hum. Genet. 1997 , 60 , 1202–1210. [ Google Scholar ]
• Roos, R.A.C. Huntington’s disease: A clinical review. Orphanet J. Rare Dis. 2010 , 5 , 1–8. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Galts, C.P.C.; Bettio, L.E.B.; Jewett, D.C.; Yang, C.C.; Brocardo, P.S.; Rodrigues, A.L.S.; Thacker, J.S.; Gil-Mohapel, J. Depression in neurodegenerative diseases: Common mechanisms and current treatment options. Neurosci. Biobehav. Rev. 2019 , 102 , 56–84. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Dorsey, E.R.; Beck, C.A.; Darwin, K.; Nichols, P.; Brocht, A.F.D.; Biglan, K.M.; Shoulson, I. Natural history of Huntington disease. JAMA Neurol. 2013 , 70 , 1520–1530. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Lanska, D.J.; Lavine, L.; Lanska, M.J.; Schoenberg, B.S. Huntington’s disease mortality in the United States. Neurology 1988 , 38 , 769–772. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Lee, J.M.; Wheeler, V.C.; Chao, M.J.; Vonsattel, J.P.G.; Pinto, R.M.; Lucente, D.; Abu-Elneel, K.; Ramos, E.M.; Mysore, J.S.; Gillis, T.; et al. Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease. Cell 2015 , 162 , 516–526. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Pringsheim, T.; Wiltshire, K.; Day, L.; Dykeman, J.; Steeves, T.; Jette, N. The incidence and prevalence of Huntington’s disease: A systematic review and meta-analysis. Mov. Disord. 2012 , 27 , 1083–1091. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kay, C.; Collins, J.A.; Wright, G.E.B.; Baine, F.; Miedzybrodzka, Z.; Aminkeng, F.; Semaka, A.J.; McDonald, C.; Davidson, M.; Madore, S.J.; et al. The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2018 , 177 , 346–357. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rawlins, M.D.; Wexler, N.S.; Wexler, A.R.; Tabrizi, S.J.; Douglas, I.; Evans, S.J.W.; Smeeth, L. The Prevalence of Huntington’s Disease. Neuroepidemiology 2016 , 46 , 144–153. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Fisher, E.R.; Hayden, M.R. Multisource ascertainment of Huntington disease in Canada: Prevalence and population at risk. Mov. Disord. 2014 , 29 , 105–114. [ Google Scholar ] [ CrossRef ]
• MacDonald, M.E.; Ambrose, C.M.; Duyao, M.P.; Myers, R.H.; Lin, C.; Srinidhi, L.; Barnes, G.; Taylor, S.A.; James, M.; Groot, N.; et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993 , 72 , 971–983. [ Google Scholar ] [ CrossRef ]
• Ochaba, J.; Lukacsovich, T.; Csikos, G.; Zheng, S.; Margulis, J.; Salazar, L.; Mao, K.; Lau, A.L.; Yeung, S.Y.; Humbert, S.; et al. Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc. Natl. Acad. Sci. USA 2014 , 111 , 16889–16894. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Liu, J.P.; Zeitlin, S.O. Is huntingtin dispensable in the adult brain? J. Huntingtons. Dis. 2017 , 6 , 1–17. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Dayalu, P.; Albin, R.L. Huntington Disease. Neurol. Clin. 2015 , 33 , 101–114. [ Google Scholar ] [ CrossRef ]
• Semaka, A.; Kay, C.; Doty, C.; Collins, J.A.; Bijlsma, E.K.; Richards, F.; Goldberg, Y.P.; Hayden, M.R. CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. J. Med. Genet. 2013 , 50 , 696–703. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Aziz, N.A.; Jurgens, C.K.; Landwehrmeyer, G.B.; Van Roon-Mom, W.M.C.; Van Ommen, G.J.B.; Stijnen, T.; Roos, R.A.C. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology 2009 , 73 , 1280–1285. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Arning, L.; Kraus, P.H.; Valentin, S.; Saft, C.; Andrich, J.; Epplen, J.T. NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenetics 2005 , 6 , 25–28. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Wexler, N.S.; Lorimer, J.; Porter, J.; Gomez, F.; Moskowitz, C.; Shackell, E.; Marder, K.; Penchaszadeh, G.; Roberts, S.A.; Gayan, J.; et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc. Natl. Acad. Sci. USA 2004 , 101 , 3498–3503. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Rüb, U.; Seidel, K.; Heinsen, H.; Vonsattel, J.P.; den Dunnen, W.F.; Korf, H.W. Huntington’s disease (HD): The neuropathology of a multisystem neurodegenerative disorder of the human brain. Brain Pathol. 2016 , 26 , 726–740. [ Google Scholar ] [ CrossRef ]
• DiFiglia, M.; Sapp, E.; Chase, K.O.; Davies, S.W.; Bates, G.P.; Vonsattel, J.P.; Aronin, N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997 , 277 , 1990–1993. [ Google Scholar ] [ CrossRef ]
• Papoutsi, M.; Labuschagne, I.; Tabrizi, S.J.; Stout, J.C. The cognitive burden in Huntington’s disease: Pathology, phenotype, and mechanisms of compensation. Mov. Disord. 2014 , 29 , 673–683. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Vonsattel, J.; Myers, R.H.; Stevens, T.J.; Ferrante, R.J.; Bird, E.D.; Richardson, E.P. Neuropathological Classification of Huntington’s Disease. J. Neuropathol. Exp. Neurol. 1985 , 44 , 559–577. [ Google Scholar ] [ CrossRef ]
• De La Monte, S.M.; Vonsattel, J.P.; Richardson, E.P. Morphometric demonstration of atrophic changes in the ceRebral cortex, white matter, and neostriatum in huntington’s disease. J. Neuropathol. Exp. Neurol. 1988 , 47 , 516–525. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Heinsen, H.; Rüb, U.; Bauer, M.; Ulmar, G.; Bethke, B.; Schüler, M.; Böcker, F.; Eisenmenger, W.; Götz, M.; Korr, H.; et al. Nerve cell loss in the thalamic mediodorsal nucleus in Huntington’s disease. Acta Neuropathol. 1999 , 97 , 613–622. [ Google Scholar ] [ CrossRef ]
• Rosas, H.D.; Liu, A.K.; Hersch, S.; Glessner, M.; Ferrante, R.J.; Salat, D.H.; Van Der Kouwe, A.; Jenkins, B.G.; Dale, A.M.; Fischl, B. Regional and progressive thinning of the cortical ribbon in Huntington’s disease. Neurology 2002 , 58 , 695–701. [ Google Scholar ] [ CrossRef ]
• Peterseén, Å.; Gil, J.; Maat-Schieman, M.L.C.; Björkqvist, M.; Tanila, H.; Araújo, I.M.; Smith, R.; Popovic, N.; Wierup, N.; Norlén, P.; et al. Orexin loss in Huntington’s disease. Hum. Mol. Genet. 2005 , 14 , 39–47. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Rüb, U.; Hoche, F.; Brunt, E.R.; Heinsen, H.; Seidel, K.; Del Turco, D.; Paulson, H.L.; Bohl, J.; Von Gall, C.; Vonsattel, J.P.; et al. Degeneration of the cerebellum in huntingtons disease (HD): Possible relevance for the clinical picture and potential gateway to pathological mechanisms of the disease process. Brain Pathol. 2013 , 23 , 165–177. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rüb, U.; Hentschel, M.; Stratmann, K.; Brunt, E.; Heinsen, H.; Seidel, K.; Bouzrou, M.; Auburger, G.; Paulson, H.; Vonsattel, J.-P.; et al. Huntington’s Disease (HD): Degeneration of Select Nuclei, Widespread Occurrence of Neuronal Nuclear and Axonal Inclusions in the Brainstem. Brain Pathol. 2014 , 24 , 247–260. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Cattaneo, E.; Zuccato, C.; Tartari, M. Normal huntingtin function: An alternative approach to Huntington’s disease. Nat. Rev. Neurosci. 2005 , 6 , 919–930. [ Google Scholar ] [ CrossRef ]
• Gil, J.M.; Rego, A.C. Mechanisms of neurodegeneration in Huntington’s disease. Eur. J. Neurosci. 2008 , 27 , 2803–2820. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Sturrock, A.; Leavitt, B.R. The clinical and genetic features of Huntington disease. J. Geriatr. Psychiatry Neurol. 2010 , 23 , 243–259. [ Google Scholar ] [ CrossRef ]
• Nance, M.A. Huntington disease: Clinical, genetic, and social aspects. J. Geriatr. Psychiatry Neurol. 1998 , 11 , 61–70. [ Google Scholar ] [ CrossRef ]
• Schiffmann, S.N.; Vanderhaeghen, J.J. Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J. Neurosci. 1993 , 13 , 1080–1087. [ Google Scholar ] [ CrossRef ]
• André, V.M.; Cepeda, C.; Levine, M.S. Dopamine and glutamate in huntington’s disease: A balancing act. CNS Neurosci. Ther. 2010 , 16 , 163–178. [ Google Scholar ] [ CrossRef ]
• Joel, D. Open interconnected model of basal ganglia-thalamocortical circuitry and its relevance to the clinical syndrome of Huntington’s disease. Mov. Disord. 2001 , 16 , 407–423. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Nelson, A.B.; Kreitzer, A.C. Reassessing Models of Basal Ganglia Function and Dysfunction. Annu. Rev. Neurosci. 2014 , 37 , 117–135. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Butters, N.; Wolfe, J.; Martone, M.; Granholm, E.; Cermak, L.S. Memory disorders associated with huntington’s disease: Verbal recall, verbal recognition and procedural memory. Neuropsychologia 1985 , 23 , 729–743. [ Google Scholar ] [ CrossRef ]
• Pillons, B.; Dubois, B.; Agid, Y. Severity and Specificity of Cognitive Impairment in Alzheimer’s, Huntington’s, and Parkinson’s Diseases and Progressive Supranuclear Palsy. Ann. N. Y. Acad. Sci. 1991 , 640 , 224–227. [ Google Scholar ] [ CrossRef ]
• Shiwach, R. Psychopathology in Huntington’s disease patients. Acta Psychiatr. Scand. 1994 , 90 , 241–246. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Di Maio, L.; Squitieri, F.; Napolitano, G.; Campanella, G.; Trofatter, J.A.; Conneally, P.M. Suicide risk in Huntington’s disease. J. Med. Genet. 1993 , 30 , 293–295. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Hirano, M.; Iritani, S.; Fujishiro, H.; Torii, Y.; Habuchi, C.; Sekiguchi, H.; Yoshida, M.; Ozaki, N. Clinicopathological differences between the motor onset and psychiatric onset of Huntington’s disease, focusing on the nucleus accumbens. Neuropathology 2019 , 39 , 331–341. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Nithianantharajah, J.; Hannan, A.J. Dysregulation of synaptic proteins, dendritic spine abnormalities and pathological plasticity of synapses as experience-dependent mediators of cognitive and psychiatric symptoms in Huntington’s disease. Neuroscience 2013 , 251 , 66–74. [ Google Scholar ] [ CrossRef ]
• Goodman, A.O.G.; Murgatroyd, P.R.; Medina-Gomez, G.; Wood, N.I.; Finer, N.; Vidal-Puig, A.J.; Morton, A.J.; Barker, R.A. The metabolic profile of early Huntington’s disease- a combined human and transgenic mouse study. Exp. Neurol. 2008 , 210 , 691–698. [ Google Scholar ] [ CrossRef ]
• Petersén, Å.; Björkqvist, M. Hypothalamic-endocrine aspects in Huntington’s disease. Eur. J. Neurosci. 2006 , 24 , 961–967. [ Google Scholar ] [ CrossRef ]
• Naia, L.; Ferreira, I.L.; Cunha-Oliveira, T.; Duarte, A.I.; Ribeiro, M.; Rosenstock, T.R.; Laço, M.N.; Ribeiro, M.J.; Oliveira, C.R.; Saudou, F.; et al. Activation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington’s Disease Human Lymphoblasts. Mol. Neurobiol. 2015 , 51 , 331–348. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Naia, L.; Ribeiro, M.; Rodrigues, J.; Duarte, A.I.; Lopes, C.; Rosenstock, T.R.; Hayden, M.R.; Rego, A.C. Insulin and IGF-1 regularize energy metabolites in neural cells expressing full-length mutant huntingtin. Neuropeptides 2016 , 58 , 73–81. [ Google Scholar ] [ CrossRef ]
• Ribeiro, M.; Rosenstock, T.R.; Oliveira, A.M.; Oliveira, C.R.; Rego, A.C. Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington’s disease knock-in striatal cells. Free Radic. Biol. Med. 2014 , 74 , 129–144. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rosenstock, T.R.; De Brito, O.M.; Lombardi, V.; Louros, S.; Ribeiro, M.; Almeida, S.; Ferreira, I.L.; Oliveira, C.R.; Rego, A.C. FK506 ameliorates cell death features in Huntington’s disease striatal cell models. Neurochem. Int. 2011 , 59 , 600–609. [ Google Scholar ] [ CrossRef ]
• Ehrlich, M.E. Huntington’s Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease. Neurotherapeutics 2012 , 9 , 270–284. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Cicchetti, F.; Prensa, L.; Wu, Y.; Parent, A. Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington’s disease. Brain Res. Rev. 2000 , 34 , 80–101. [ Google Scholar ] [ CrossRef ]
• Landwehrmeyer, G.B.; Standaert, D.G.; Testa, C.M.; Penney, J.B.; Young, A.B. NMDA receptor subunit mRNA expression by projection neurons and interneurons in rat striatum. J. Neurosci. 1995 , 15 , 5297–5307. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Sieradzan, K.A.; Mann, D.M.A. The selective vulnerability of nerve cells in Huntington’s disease. Neuropathol. Appl. Neurobiol. 2001 , 27 , 1–21. [ Google Scholar ] [ CrossRef ]
• Zeron, M.M.; Chen, N.; Moshaver, A.; Ting-Chun Lee, A.; Wellington, C.L.; Hayden, M.R.; Raymond, L.A. Mutant huntingtin enhances excitotoxic cell death. Mol. Cell. Neurosci. 2001 , 17 , 41–53. [ Google Scholar ] [ CrossRef ]
• Heng, M.Y.; Detloff, P.J.; Wang, P.L.; Tsien, J.Z.; Albin, R.L. In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of huntington disease. J. Neurosci. 2009 , 29 , 3200–3205. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Storey, E.; Kowall, N.W.; Finn, S.F.; Mazurek, M.F.; Beal, M.F. The cortical lesion of Huntington’s disease: Further neurochemical characterization, and reproduction of some of the histological and neurochemical features byN-methyl-D-aspartate lesions of rat cortex. Ann. Neurol. 1992 , 32 , 526–534. [ Google Scholar ] [ CrossRef ]
• Arzberger, T.; Krampfl, K.; Leimgruber, S.; Weindl, A. Changes of NMDA receptor subunit (NR1, NR2B) and glutamate transporter (GLT1) mRNA expression in Huntington’s disease—An in situ hybridization study. J. Neuropathol. Exp. Neurol. 1997 , 56 , 440–454. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Liévens, J.C.; Woodman, B.; Mahal, A.; Spasic-Boscovic, O.; Samuel, D.; Kerkerian-Le Goff, L.; Bates, G.P. Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol. Dis. 2001 , 8 , 807–821. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Shin, J.Y.; Fang, Z.H.; Yu, Z.X.; Wang, C.E.; Li, S.H.; Li, X.J. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 2005 , 171 , 1001–1012. [ Google Scholar ] [ CrossRef ]
• Lee, W.; Reyes, R.C.; Gottipati, M.K.; Lewis, K.; Lesort, M.; Parpura, V.; Gray, M. Enhanced Ca 2+ -dependent glutamate release from astrocytes of the BACHD Huntington’s disease mouse model. Neurobiol. Dis. 2013 , 58 , 192–199. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Palpagama, T.H.; Waldvogel, H.J.; Faull, R.L.M.; Kwakowsky, A. The Role of Microglia and Astrocytes in Huntington’s Disease. Front. Mol. Neurosci. 2019 , 12 , 258. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Schwarcz, R.; Guidetti, P.; Sathyasaikumar, K.V.; Muchowski, P.J. Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington’s disease. Prog. Neurobiol. 2010 , 90 , 230–245. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Rosenstock, T.R.; Duarte, A.I.; Cristina Rego, A. Mitochondrial-Associated Metabolic Changes and Neurodegeneration in Huntingtons Disease—From Clinical Features to the Bench. Curr. Drug Targets 2010 , 11 , 1218–1236. [ Google Scholar ] [ CrossRef ]
• Garrett, M.C.; Soares-da-Silva, P. Increased Cerebrospinal Fluid Dopamine and 3,4-Dihydroxyphenylacetic Acid Levels in Huntington’s Disease: Evidence for an Overactive Dopaminergic Brain Transmission. J. Neurochem. 1992 , 58 , 101–106. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kish, S.J.; Shannak, K.; Hornykiewicz, O. Elevated serotonin and reduced dopamine in subregionally divided Huntington’s disease striatum. Ann. Neurol. 1987 , 22 , 386–389. [ Google Scholar ] [ CrossRef ]
• Weeks, R.A.; Piccini, P.; Harding, A.E.; Brooks, D.J. Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington’s disease. Ann. Neurol. 1996 , 40 , 49–54. [ Google Scholar ] [ CrossRef ]
• Yohrling, G.J., IV; Jiang, G.C.T.; De John, M.M.; Miller, D.W.; Young, A.B.; Vrana, K.E.; Cha, J.H.J. Analysis of cellular, transgenic and human models of Huntington’s disease reveals tyrosine hydroxylase alterations and substantia nigra neuropathology. Mol. Brain Res. 2003 , 119 , 28–36. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Charvin, D.; Vanhoutte, P.; Pagès, C.; Borelli, E.; Caboche, J. Unraveling a role for dopamine in Huntington’s disease: The dual role of reactive oxygen species and D2 receptor stimulation. Proc. Natl. Acad. Sci. USA 2005 , 102 , 12218–12223. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Vidoni, C.; Castiglioni, A.; Seca, C.; Secomandi, E.; Melone, M.A.B.; Isidoro, C. Dopamine exacerbates mutant Huntingtin toxicity via oxidative-mediated inhibition of autophagy in SH-SY5Y neuroblastoma cells: Beneficial effects of anti-oxidant therapeutics. Neurochem. Int. 2016 , 101 , 132–143. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sulzer, D.; Zecca, L. Intraneuronal dopamine-quinone synthesis: A review. Neurotox. Res. 1999 , 1 , 181–195. [ Google Scholar ] [ CrossRef ]
• Miyazaki, I.; Asanuma, M. Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity. Neurochem. Res. 2009 , 34 , 698–706. [ Google Scholar ] [ CrossRef ]
• Carmo, C.; Naia, L.; Lopes, C.; Rego, A.C. Mitochondrial Dysfunction in Huntington’s Disease. In Advances in Experimental Medicine and Biology ; Springer New York LLC: New York, NY, USA, 2018; Volume 1049, pp. 59–83. [ Google Scholar ]
• Kim, J.; Moody, J.P.; Edgerly, C.K.; Bordiuk, O.L.; Cormier, K.; Smith, K.; Flint Beal, M.; Ferrante, R.J. Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum. Mol. Genet. 2010 , 19 , 3919–3935. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Panov, A.V.; Gutekunst, C.A.; Leavitt, B.R.; Hayden, M.R.; Burke, J.R.; Strittmatter, W.J.; Greenamyre, J.T. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat. Neurosci. 2002 , 5 , 731–736. [ Google Scholar ] [ CrossRef ]
• Song, W.; Chen, J.; Petrilli, A.; Liot, G.; Klinglmayr, E.; Zhou, Y.; Poquiz, P.; Tjong, J.; Pouladi, M.A.; Hayden, M.R.; et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat. Med. 2011 , 17 , 377–383. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Knott, A.B.; Perkins, G.; Schwarzenbacher, R.; Bossy-Wetzel, E. Mitochondrial fragmentation in neurodegeneration. Nat. Rev. Neurosci. 2008 , 9 , 505–518. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Knott, A.B.; Bossy-Wetzel, E. Impairing the Mitochondrial Fission and Fusion Balance: A New Mechanism of Neurodegeneration. Ann. N. Y. Acad. Sci. 2008 , 1147 , 283–292. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Okamoto, S.I.; Pouladi, M.A.; Talantova, M.; Yao, D.; Xia, P.; Ehrnhoefer, D.E.; Zaidi, R.; Clemente, A.; Kaul, M.; Graham, R.K.; et al. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat. Med. 2009 , 15 , 1407–1413. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Cui, L.; Jeong, H.; Borovecki, F.; Parkhurst, C.N.; Tanese, N.; Krainc, D. Transcriptional Repression of PGC-1α by Mutant Huntingtin Leads to Mitochondrial Dysfunction and Neurodegeneration. Cell 2006 , 127 , 59–69. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Mealer, R.G.; Murray, A.J.; Shahani, N.; Subramaniam, S.; Snyder, S.H. Rhes, a Striatal-selective Protein Implicated in Huntington Disease, Binds Beclin-1 and activates autophagy. J. Biol. Chem. 2014 , 289 , 3547–3554. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Johri, A.; Chandra, A.; Beal, M.F. PGC-1α, mitochondrial dysfunction, and Huntington’s disease. Free Radic. Biol. Med. 2013 , 62 , 37–46. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Lin, J.; Handschin, C.; Spiegelman, B.M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005 , 1 , 361–370. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Perluigi, M.; Poon, H.F.; Maragos, W.; Pierce, W.M.; Klein, J.B.; Calabrese, V.; Cini, C.; De Marco, C.; Butterfield, D.A. Proteomic Analysis of Protein Expression and Oxidative Modification in R6/2 Transgenic Mice. Mol. Cell. Proteomics 2005 , 4 , 1849–1861. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Weydt, P.; Pineda, V.V.; Torrence, A.E.; Libby, R.T.; Satterfield, T.F.; Lazarowski, E.R.R.; Gilbert, M.L.; Morton, G.J.; Bammler, T.K.; Strand, A.D.; et al. Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1α in Huntington’s disease neurodegeneration. Cell Metab. 2006 , 4 , 349–362. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Weydt, P.; Dupuis, L.; Petersen, Å. Thermoregulatory disorders in Huntington disease. In Handbook of Clinical Neurology ; Elsevier B.V.: Amsterdam, The Netherlands, 2018; Volume 157, pp. 761–775. ISBN 9780444640741. [ Google Scholar ]
• Browne, S.E.; Beal, M.F. The Energetics of Huntington’s Disease. Neurochem. Res. 2004 , 29 , 531–546. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Chen, C.M.; Wu, Y.R.; Cheng, M.L.; Liu, J.L.; Lee, Y.M.; Lee, P.W.; Soong, B.W.; Chiu, D.T.Y. Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington’s disease patients. Biochem. Biophys. Res. Commun. 2007 , 359 , 335–340. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Altlner, Ş.; Ardic, S.; Çebi, A.H. Extending the Phenotypic Spectrum of Huntington Disease: Hypothermia. Mol. Syndromol. 2020 , 11 , 56–58. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Terman, A.; Kurz, T.; Navratil, M.; Arriaga, E.A.; Brunk, U.T. Mitochondrial Turnover and aging of long-lived postmitotic cells: The mitochondrial-lysosomal axis theory of aging. Antioxid. Redox Signal. 2010 , 12 , 503–535. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Martinez-Vicente, M. Autophagy in neurodegenerative diseases: From pathogenic dysfunction to therapeutic modulation. Semin. Cell Dev. Biol. 2015 , 40 , 115–126. [ Google Scholar ] [ CrossRef ]
• Weihl, C.C. Monitoring Autophagy in the Treatment of Protein Aggregate Diseases: Steps Toward Identifying Autophagic Biomarkers. Neurotherapeutics 2013 , 10 , 383–390. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Pircs, K.; Petri, R.; Madsen, S.; Brattås, P.L.; Vuono, R.; Ottosson, D.R.; St-Amour, I.; Hersbach, B.A.; Matusiak-Brückner, M.; Lundh, S.H.; et al. Huntingtin Aggregation Impairs Autophagy, Leading to Argonaute-2 Accumulation and Global MicroRNA Dysregulation. Cell Rep. 2018 , 24 , 1397–1406. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Ravikumar, B.; Vacher, C.; Berger, Z.; Davies, J.E.; Luo, S.; Oroz, L.G.; Scaravilli, F.; Easton, D.F.; Duden, R.; O’Kane, C.J.; et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 2004 , 36 , 585–595. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Martinez-Vicente, M.; Talloczy, Z.; Wong, E.; Tang, G.; Koga, H.; Kaushik, S.; De Vries, R.; Arias, E.; Harris, S.; Sulzer, D.; et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat. Neurosci. 2010 , 13 , 567–576. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Rui, Y.N.; Xu, Z.; Patel, B.; Chen, Z.; Chen, D.; Tito, A.; David, G.; Sun, Y.; Stimming, E.F.; Bellen, H.J.; et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat. Cell Biol. 2015 , 17 , 262–275. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Koga, H.; Martinez-Vicente, M.; Arias, E.; Kaushik, S.; Sulzer, D.; Cuervo, A.M. Constitutive upregulation of chaperone-mediated autophagy in Huntington’s disease. J. Neurosci. 2011 , 31 , 18492–18505. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Cortes, C.J.; La Spada, A.R. The many faces of autophagy dysfunction in Huntington’s disease: From mechanism to therapy. Drug Discov. Today 2014 , 19 , 963–971. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Kamat, P.K.; Kalani, A.; Kyles, P.; Tyagi, S.C.; Tyagi, N. Autophagy of Mitochondria: A Promising Therapeutic Target for Neurodegenerative Disease. Cell Biochem. Biophys. 2014 , 70 , 707–719. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Anthony Altar, C.; Cai, N.; Bliven, T.; Juhasz, M.; Conner, J.M.; Acheson, A.L.; Lindsay, R.M.; Wiegand, S.J. Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 1997 , 389 , 856–860. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Baquet, Z.C.; Gorski, J.A.; Jones, K.R. Early Striatal Dendrite Deficits followed by Neuron Loss with Advanced Age in the Absence of Anterograde Cortical Brain-Derived Neurotrophic Factor. J. Neurosci. 2004 , 24 , 4250–4258. [ Google Scholar ] [ CrossRef ]
• Hofer, M.; Pagliusi, S.R.; Hohn, A.; Leibrock, J.; Barde, Y.A. Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain. EMBO J. 1990 , 9 , 2459–2464. [ Google Scholar ] [ CrossRef ]
• Adachi, N. New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases. World J. Biol. Chem. 2014 , 5 , 409. [ Google Scholar ] [ CrossRef ]
• Chao, M.V.; Hempstead, B.L. p75 and Trk: A two-receptor system. Trends Neurosci. 1995 , 18 , 321–326. [ Google Scholar ] [ CrossRef ]
• Sugimoto, T.; Kuroda, H.; Horii, Y.; Moritake, H.; Tanaka, T.; Hattori, S. Signal transduction pathways through TRK-A and TRK-B receptors in human neuroblastoma cells. Jpn. J. Cancer Res. 2001 , 92 , 152–160. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Yuen, E.C.; Mobley, W.C. Early BDNF, NT-3, and NT-4 signaling events. Exp. Neurol. 1999 , 159 , 297–308. [ Google Scholar ] [ CrossRef ]
• Roux, P. Neurotrophin signaling through the p75 neurotrophin receptor. Prog. Neurobiol. 2002 , 67 , 203–233. [ Google Scholar ] [ CrossRef ]
• Zuccato, C. Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington’s Disease. Science 2001 , 293 , 493–498. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Gauthier, L.R.; Charrin, B.C.; Borrell-Pagès, M.; Dompierre, J.P.; Rangone, H.; Cordelières, F.P.; De Mey, J.; MacDonald, M.E.; Leßmann, V.; Humbert, S.; et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 2004 , 118 , 127–138. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Yu, C.; Li, C.H.; Chen, S.; Yoo, H.; Qin, X.; Park, H. Decreased BDNF Release in Cortical Neurons of a Knock-in Mouse Model of Huntington’s Disease. Sci. Rep. 2018 , 8 , 1–11. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Duan, W.; Guo, Z.; Jiang, H.; Ware, M.; Li, X.J.; Mattson, M.P. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc. Natl. Acad. Sci. USA 2003 , 100 , 2911–2916. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Gines, S.; Seong, I.S.; Fossale, E.; Ivanova, E.; Trettel, F.; Gusella, J.F.; Wheeler, V.C.; Persichetti, F.; MacDonald, M.E. Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington’s disease knock-in mice. Hum. Mol. Genet. 2003 , 12 , 497–508. [ Google Scholar ] [ CrossRef ]
• Giralt, A.; Carretán, O.; Lao-Peregrin, C.; Martín, E.D.; Alberch, J. Conditional BDNF release under pathological conditions improves Huntington’s disease pathology by delaying neuronal dysfunction. Mol. Neurodegener. 2011 , 6 , 1–16. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Jin, J.; Peng, Q.; Hou, Z.; Jiang, M.; Wang, X.; Langseth, A.J.; Tao, M.; Barker, P.B.; Mori, S.; Bergles, D.E.; et al. Early white matter abnormalities, progressive brain pathology and motor deficits in a novel knock-in mouse model of Huntington’s disease. Hum. Mol. Genet. 2015 , 24 , 2508–2527. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Pang, T.Y.C.; Stam, N.C.; Nithianantharajah, J.; Howard, M.L.; Hannan, A.J. Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in huntington’s disease transgenic mice. Neuroscience 2006 , 141 , 569–584. [ Google Scholar ] [ CrossRef ]
• Peng, Q.; Masuda, N.; Jiang, M.; Li, Q.; Zhao, M.; Ross, C.A.; Duan, W. The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington’s disease mouse model. Exp. Neurol. 2008 , 210 , 154–163. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Spires, T.L.; Grote, H.E.; Garry, S.; Cordery, P.M.; Van Dellen, A.; Blakemore, C.; Hannan, A.J. Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington’s disease transgenic mice. Eur. J. Neurosci. 2004 , 19 , 2799–2807. [ Google Scholar ] [ CrossRef ]
• Suelves, N.; Miguez, A.; López-Benito, S.; Barriga, G.G.D.; Giralt, A.; Alvarez-Periel, E.; Arévalo, J.C.; Alberch, J.; Ginés, S.; Brito, V. Early Downregulation of p75 NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington’s Disease Mice. Mol. Neurobiol. 2019 , 56 , 935–953. [ Google Scholar ] [ CrossRef ]
• Ciammola, A.; Sassone, J.; Cannella, M.; Calza, S.; Poletti, B.; Frati, L.; Squitieri, F.; Silani, V. Low brain-derived neurotrophic factor (BDNF) levels in serum of Huntington’s disease patients. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2007 , 144 , 574–577. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Krzysztoń-Russjan, J.; Zielonka, D.; Jackiewicz, J.; Kuåmirek, S.; Bubko, I.; Klimberg, A.; Marcinkowski, J.T.; Anuszewska, E.L. A study of molecular changes relating to energy metabolism and cellular stress in people with Huntington’s disease: Looking for biomarkers. J. Bioenerg. Biomembr. 2013 , 45 , 71–85. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Ferrer, I.; Goutan, E.; Marín, C.; Rey, M.J.; Ribalta, T. Brain-derived neurotrophic factor in Huntington disease. Brain Res. 2000 , 866 , 257–261. [ Google Scholar ] [ CrossRef ]
• Seo, H.; Sonntag, K.C.; Isacson, O. Generalized brain and skin proteasome inhibition in Huntington’s disease. Ann. Neurol. 2004 , 56 , 319–328. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Zuccato, C.; Marullo, M.; Conforti, P.; MacDonald, M.E.; Tartari, M.; Cattaneo, E. Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington’s disease. Brain Pathol. 2008 , 18 , 225–238. [ Google Scholar ] [ CrossRef ]
• Squitieri, F.; Orobello, S.; Cannella, M.; Martino, T.; Romanelli, P.; Giovacchini, G.; Frati, L.; Mansi, L.; Ciarmiello, A. Riluzole protects Huntington disease patients from brain glucose hypometabolism and grey matter volume loss and increases production of neurotrophins. Eur. J. Nucl. Med. Mol. Imaging 2009 , 36 , 1113–1120. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Pan, W.; Banks, W.A.; Kastin, A.J. Permeability of the blood-brain barrier to neurotrophins. Brain Res. 1998 , 788 , 87–94. [ Google Scholar ] [ CrossRef ]
• Pan, W.; Banks, W.A.; Fasold, M.B.; Bluth, J.; Kastin, A.J. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 1998 , 37 , 1553–1561. [ Google Scholar ] [ CrossRef ]
• Karege, F.; Schwald, M.; Cisse, M. Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci. Lett. 2002 , 328 , 261–264. [ Google Scholar ] [ CrossRef ]
• Zuccato, C.; Cattaneo, E. Role of brain-derived neurotrophic factor in Huntington’s disease. Prog. Neurobiol. 2007 , 81 , 294–330. [ Google Scholar ] [ CrossRef ]
• Menalled, L.B.; Chesselet, M.-F. Mouse models of Huntington’s disease. Trends Pharmacol. Sci. 2002 , 23 , 32–39. [ Google Scholar ] [ CrossRef ]
• Hickey, M.A.; Chesselet, M.F. The use of transgenic and knock-in mice to study Huntington’s disease. Cytogenet. Genome Res. 2003 , 100 , 276–286. [ Google Scholar ] [ CrossRef ]
• Levine, M.S.; Cepeda, C.; Hickey, M.A.; Fleming, S.M.; Chesselet, M.F. Genetic mouse models of Huntington’s and Parkinson’s diseases: Illuminating but imperfect. Trends Neurosci. 2004 , 27 , 691–697. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Gil, J.M.; Rego, A.C. The R6 lines of transgenic mice: A model for screening new therapies for Huntington’s disease. Brain Res. Rev. 2009 , 59 , 410–431. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Gil-Mohapel, J.M. Screening of therapeutic strategies for Huntington’s disease in YAC128 transgenic mice. CNS Neurosci. Ther. 2012 , 18 , 77–86. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Farshim, P.P.; Bates, G.P. Mouse Models of Huntington’s Disease. In Methods in Molecular Biology ; Humana Press Inc.: Totowa, NJ, USA, 2018; Volume 1780, pp. 97–120. [ Google Scholar ]
• Mangiarini, L.; Sathasivam, K.; Seller, M.; Cozens, B.; Harper, A.; Hetherington, C.; Lawton, M.; Trottier, Y.; Lehrach, H.; Davies, S.W.; et al. Exon I of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996 , 87 , 493–506. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Lione, L.A.; Carter, R.J.; Hunt, M.J.; Bates, G.P.; Morton, A.J.; Dunnett, S.B. Selective discrimination learning impairments in mice expressing the human Huntington’s disease mutation. J. Neurosci. 1999 , 19 , 10428–10437. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Carter, R.J.; Lione, L.A.; Humby, T.; Mangiarini, L.; Mahal, A.; Bates, G.P.; Dunnett, S.B.; Morton, A.J. Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation. J. Neurosci. 1999 , 19 , 3248–3257. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Davies, S.W.; Turmaine, M.; Cozens, B.A.; Di Figlia, M.; Sharp, A.H.; Ross, C.A.; Scherzinger, E.; Wanker, E.E.; Mangiarini, L.; Bates, G.P. Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation. Cell 1997 , 90 , 537–548. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Dodds, L.; Chen, J.; Berggren, K.; Fox, J. Characterization of Striatal Neuronal Loss and Atrophy in the R6/2 Mouse Model of Huntington’s Disease. PLoS Curr. 2014 . [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Stack, E.C.; Kubilus, J.K.; Smith, K.; Cormier, K.; Del Signore, S.J.; Guelin, E.; Ryu, H.; Hersch, S.M.; Ferrante, R.J. Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington’s disease transgenic mice. J. Comp. Neurol. 2005 , 490 , 354–370. [ Google Scholar ] [ CrossRef ]
• Schilling, G.; Becher, M.W.; Sharp, A.H.; Jinnah, H.A.; Duan, K.; Kotzuk, J.A.; Slunt, H.H.; Ratovitski, T.; Cooper, J.K.; Jenkins, N.A.; et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 1999 , 8 , 397–407. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Cheng, Y.; Peng, Q.; Hou, Z.; Aggarwal, M.; Zhang, J.; Mori, S.; Ross, C.A.; Duan, W. Structural MRI detects progressive regional brain atrophy and neuroprotective effects in N171-82Q Huntington’s disease mouse model. Neuroimage 2011 , 56 , 1027–1034. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Yu, Z.X.; Li, S.H.; Evans, J.; Pillarisetti, A.; Li, H.; Li, X.J. Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington’s disease. J. Neurosci. 2003 , 23 , 2193–2202. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Southwell, A.L.; Ko, J.; Patterson, P.H. Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington’s disease. J. Neurosci. 2009 , 29 , 13589–13602. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Slow, E.J.; van Raamsdonk, J.; Rogers, D.; Coleman, S.H.; Graham, R.K.; Deng, Y.; Oh, R.; Bissada, N.; Hossain, S.M.; Yang, Y.Z.; et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum. Mol. Genet. 2003 , 12 , 1555–1567. [ Google Scholar ] [ CrossRef ]
• Pouladi, M.A.; Graham, R.K.; Karasinska, J.M.; Xie, Y.; Santos, R.D.; Petersn, Â.; Hayden, M.R. Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin. Brain 2009 , 132 , 919–932. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Brooks, S.; Higgs, G.; Janghra, N.; Jones, L.; Dunnett, S.B. Longitudinal analysis of the behavioural phenotype in YAC128 (C57BL/6J) Huntington’s disease transgenic mice. Brain Res. Bull. 2012 , 88 , 113–120. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Van Raamsdonk, J.M.; Murphy, Z.; Slow, E.J.; Leavitt, B.R.; Hayden, M.R. Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease. Hum. Mol. Genet. 2005 , 14 , 3823–3835. [ Google Scholar ] [ CrossRef ]
• Bayram-Weston, Z.; Jones, L.; Dunnett, S.B.; Brooks, S.P. Light and electron microscopic characterization of the evolution of cellular pathology in YAC128 Huntington’s disease transgenic mice. Brain Res. Bull. 2012 , 88 , 137–147. [ Google Scholar ] [ CrossRef ]
• Pouladi, M.A.; Stanek, L.M.; Xie, Y.; Franciosi, S.; Southwell, A.L.; Deng, Y.; Butland, S.; Zhang, W.; Cheng, S.H.; Shihabuddin, L.S.; et al. Marked differences in neurochemistry and aggregates despite similar behavioural and neuropathological features of Huntington disease in the full-length BACHD and YAC128 mice. Hum. Mol. Genet. 2012 , 21 , 2219–2232. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Gray, M.; Shirasaki, D.I.; Cepeda, C.; André, V.M.; Wilburn, B.; Lu, X.H.; Tao, J.; Yamazaki, I.; Li, S.H.; Sun, Y.E.; et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neurosci. 2008 , 28 , 6182–6195. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Spampanato, J.; Gu, X.; Yang, X.W.; Mody, I. Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington’s disease. Neuroscience 2008 , 157 , 606–620. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Southwell, A.L.; Skotte, N.H.; Villanueva, E.B.; Østergaard, M.E.; Gu, X.; Kordasiewicz, H.B.; Kay, C.; Cheung, D.; Xie, Y.; Waltl, S.; et al. A novel humanizedmouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles. Hum. Mol. Genet. 2017 , 26 , 1115–1132. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Southwell, A.L.; Warby, S.C.; Carroll, J.B.; Doty, C.N.; Skotte, N.H.; Zhang, W.; Villanueva, E.B.; Kovalik, V.; Xie, Y.; Pouladi, M.A.; et al. A fully humanized transgenic mouse model of Huntington disease. Hum. Mol. Genet. 2013 , 22 , 18–34. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Menalled, L.B. Knock-in mouse models of Huntington’s disease. NeuroRx 2005 , 2 , 465–470. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Lin, C.H.; Tallaksen-Greene, S.; Chien, W.M.; Cearley, J.A.; Jackson, W.S.; Crouse, A.B.; Ren, S.; Li, X.J.; Albin, R.L.; Detloff, P.J. Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum. Mol. Genet. 2001 , 10 , 137–144. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Menalled, L.B.; Kudwa, A.E.; Miller, S.; Fitzpatrick, J.; Watson-Johnson, J.; Keating, N.; Ruiz, M.; Mushlin, R.; Alosio, W.; McConnell, K.; et al. Comprehensive Behavioral and Molecular Characterization of a New Knock-In Mouse Model of Huntington’s Disease: ZQ175. PLoS ONE 2012 , 7 , e49838. [ Google Scholar ] [ CrossRef ]
• Peng, Q.; Wu, B.; Jiang, M.; Jin, J.; Hou, Z.; Zheng, J.; Zhang, J.; Duan, W. Characterization of behavioral, neuropathological, brain metabolic and key molecular changes in zQ175 knock-in mouse model of huntington’s disease. PLoS ONE 2016 , 11 , e0148839. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Kumar, A.; Kumar, V.; Singh, K.; Kumar, S.; Kim, Y.; Lee, Y.-M.; Kim, J.-J. Therapeutic Advances for Huntington’s Disease. Brain Sci. 2020 , 10 , 43. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Stahl, C.M.; Feigin, A. Medical, Surgical, and Genetic Treatment of Huntington Disease. Neurol. Clin. 2020 , 38 , 367–378. [ Google Scholar ] [ CrossRef ]
• Pan, L.; Feigin, A. Huntington’s Disease: New Frontiers in Therapeutics. Curr. Neurol. Neurosci. Rep. 2021 , 21 , 10. [ Google Scholar ] [ CrossRef ]
• Shannon, K.M. Recent Advances in the Treatment of Huntington’s Disease: Targeting DNA and RNA. CNS Drugs 2020 , 34 , 219–228. [ Google Scholar ] [ CrossRef ]
• Beatriz, M.; Lopes, C.; Ribeiro, A.C.S.; Rego, A.C.C. Revisiting cell and gene therapies in Huntington’s disease. J. Neurosci. Res. 2021 , 1–19. [ Google Scholar ] [ CrossRef ]
• Wyant, K.J.; Ridder, A.J.; Dayalu, P. Huntington’s Disease—Update on Treatments. Curr. Neurol. Neurosci. Rep. 2017 , 17 , 33. [ Google Scholar ] [ CrossRef ]
• Potkin, K.T.; Potkin, S.G. New directions in therapeutics for Huntington disease. Future Neurol. 2018 , 13 , 101–121. [ Google Scholar ] [ CrossRef ]
• Armstrong, M.J.; Miyasaki, J.M. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease: Report of the guideline development subcommittee of the American academy of neurology. Neurology 2012 , 79 , 597–603. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial. Neurology 2006 , 66 , 366–372. [ Google Scholar ] [ CrossRef ]
• Frank, S.; Ondo, W.; Fahn, S.; Hunter, C.; Oakes, D.; Plumb, S.; Marshall, F.; Shoulson, I.; Eberly, S.; Walker, F.; et al. A study of chorea after tetrabenazine withdrawal in patients with Huntington disease. Clin. Neuropharmacol. 2008 , 31 , 127–133. [ Google Scholar ] [ CrossRef ]
• Paulsen, J.S.; Hoth, K.F.; Nehl, C.; Stierman, L. Critical periods of suicide risk in Huntington’s disease. Am. J. Psychiatry 2005 , 162 , 725–731. [ Google Scholar ] [ CrossRef ]
• Huntington Study Group Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease. JAMA 2016 , 316 , 40. [ CrossRef ] [ PubMed ] [ Green Version ]
• Burgunder, J.-M.; Guttman, M.; Perlman, S.; Goodman, N.; van Kammen, D.P.; Goodman, L. An International Survey-based Algorithm for the Pharmacologic Treatment of Chorea in Huntington’s Disease. PLoS Curr. 2011 , 3 , RRN1260. [ Google Scholar ] [ CrossRef ]
• Coppen, E.M.; Roos, R.A.C. Current Pharmacological Approaches to Reduce Chorea in Huntington’s Disease. Drugs 2017 , 77 , 29–46. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Dallocchio, C.; Buffa, C.; Tinelli, C.; Mazzarello, P. Effectiveness of Risperidone in Huntington Chorea Patients. J. Clin. Psychopharmacol. 1999 , 19 , 101–103. [ Google Scholar ] [ CrossRef ]
• Bonelli, R.; Wenning, G. Pharmacological Management of Huntingtons Disease: An Evidence- Based Review. Curr. Pharm. Des. 2006 , 12 , 2701–2720. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bonelli, R.M.; Mahnert, F.A.; Niederwieser, G. Olanzapine for Huntington’s Disease: An Open Label Study. Clin. Neuropharmacol. 2002 , 25 , 263–265. [ Google Scholar ] [ CrossRef ]
• Ciammola, A.; Sassone, J.; Colciago, C.; Mencacci, N.E.; Poletti, B.; Ciarmiello, A.; Squitieri, F.; Silani, V. Aripiprazole in the treatment of Huntington’s disease: A case series. Neuropsychiatr. Dis. Treat. 2009 , 5 , 1–4. [ Google Scholar ] [ PubMed ]
• Brusa, L.; Orlacchio, A.; Moschella, V.; Iani, C.; Bernardi, G.; Mercuri, N.B. Treatment of the symptoms of Huntington’s disease: Preliminary results comparing aripiprazole and tetrabenazine. Mov. Disord. 2009 , 24 , 126–129. [ Google Scholar ] [ CrossRef ]
• Madhusoodanan, S.; Brenner, R. Use of Risperidone in Psychosis Associated With Huntington’s Disease. Am. J. Geriatr. Psychiatry 1998 , 6 , 347–349. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Erdemoglu, A.K.; Boratav, C. Risperidone in chorea and psychosis of Huntington’s disease. Eur. J. Neurol. 2002 , 9 , 182–183. [ Google Scholar ] [ CrossRef ]
• Cankurtaran, E.S.; Ozalp, E.; Soygur, H.; Cakir, A. Clinical experience with risperidone and memantine in the treatment of Huntington’s disease. J. Natl. Med. Assoc. 2006 , 98 , 1353–1355. [ Google Scholar ] [ PubMed ]
• Reveley, M.A.; Dursun, S.M.; Andrews, H. A comparative trial use of sulpiride and risperidone in Huntington’s disease: A pilot study. J. Psychopharmacol. 1996 , 10 , 162–165. [ Google Scholar ] [ CrossRef ]
• Lucetti, C.; Gambaccini, G.; Bernardini, S.; Dell’Agnello, G.; Petrozzi, L.; Rossi, G.; Bonuccelli, U. Amantadine in Huntington’s disease: Open-label video-blinded study. Neurol. Sci. 2002 , 23 , s83–s84. [ Google Scholar ] [ CrossRef ]
• Lucetti, C.; Del Dotto, P.; Gambaccini, G.; Dell’ Agnello, G.; Bernardini, S.; Rossi, G.; Murri, L.; Bonuccelli, U. IV amantadine improves chorea in Huntington’s disease: An acute randomized, controlled study. Neurology 2003 , 60 , 1995–1997. [ Google Scholar ] [ CrossRef ]
• Metman, L.V.; Morris, M.J.; Farmer, C.; Gillespie, M.; Mosby, K.; Wuu, J.; Chase, T.N. Huntington’s disease: A randomized, controlled trial using the NMDA-antagonist amantadine. Neurology 2002 , 59 , 694–699. [ Google Scholar ] [ CrossRef ]
• O’Suilleabhain, P.; Dewey, R.B. A randomized trial of amantadine in Huntington disease. Arch. Neurol. 2003 , 60 , 996–998. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Huntington Study Group. Dosage effects of riluzole in Huntington’s disease: A multicenter placebo-controlled study. Neurology 2003 , 61 , 1551–1556. [ Google Scholar ] [ CrossRef ]
• Landwehrmeyer, G.B.; Dubois, B.; De Yébenes, J.G.; Kremer, B.; Gaus, W.; Kraus, P.H.; Przuntek, H.; Dib, M.; Doble, A.; Fischer, W.; et al. Riluzole in Huntington’s disease: A 3-year, randomized controlled study. Ann. Neurol. 2007 , 62 , 262–272. [ Google Scholar ] [ CrossRef ]
• Racette, B.A.; Perlmutter, J.S. Levodopa responsive parkinsonism in an adult with Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 1998 , 65 , 577–579. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Glidden, A.M.; Luebbe, E.A.; Elson, M.J.; Goldenthal, S.B.; Snyder, C.W.; Zizzi, C.E.; Dorsey, E.R.; Heatwole, C.R. Patient-reported impact of symptoms in Huntington disease: PRISM-HD. Neurology 2020 , 94 , e2045–e2053. [ Google Scholar ] [ CrossRef ]
• Paulsen, J.S.; Butters, N.; Sadek, J.R.; Johnson, S.A.; Salmon, D.P.; Swerdlow, N.R.; Swenson, M.R. Distinct cognitive profiles of cortical and subcortical dementia in advanced illness. Neurology 1995 , 45 , 951–956. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Hoth, K.F.; Paulsen, J.S.; Moser, D.J.; Tranel, D.; Clark, L.A.; Bechara, A. Patients with Huntington’s disease have impaired awareness of cognitive, emotional, and functional abilities. J. Clin. Exp. Neuropsychol. 2007 , 29 , 365–376. [ Google Scholar ] [ CrossRef ]
• Fernandez, H.H.; Friedman, J.H.; Grace, J.; Beason-Hazen, S. Donepezil for Huntington’s disease. Mov. Disord. 2000 , 15 , 173–176. [ Google Scholar ] [ CrossRef ]
• Rot, U.; Kobal, J.; Sever, A.; Pirtosek, Z.; Mesec, A. Rivastigmine in the treatment of Huntington’s disease. Eur. J. Neurol. 2002 , 9 , 689–690. [ Google Scholar ] [ CrossRef ]
• De Tommaso, M.; Specchio, N.; Sciruicchio, V.; Difruscolo, O.; Specchio, L.M. Effects of rivastigmine on motor and cognitive impairment in Huntington’s disease. Mov. Disord. 2004 , 19 , 1516–1518. [ Google Scholar ] [ CrossRef ]
• Petrikis, P.; Andreou, C.; Piachas, A.; Bozikas, V.P.; Karavatos, A. Treatment of Huntington’s disease with galantamine. Int. Clin. Psychopharmacol. 2004 , 19 , 49–50. [ Google Scholar ] [ CrossRef ]
• Ondo, W.G.; Mejia, N.I.; Hunter, C.B. A pilot study of the clinical efficacy and safety of memantine for Huntington’s disease. Parkinsonism Relat. Disord. 2007 , 13 , 453–454. [ Google Scholar ] [ CrossRef ]
• Beister, A.; Kraus, P.; Kuhn, W.; Dose, M.; Weindl, A.; Gerlach, M. The N-methyl-D-aspartate antagonist memantine retards progression of Huntington’s disease. J. Neural Transm. Suppl. 2004 , 117–122. [ Google Scholar ] [ CrossRef ]
• Van Duijn, E.; Kingma, E.M.; Van Der Mast, R.C. Psychopathology in verified Huntington’s disease gene carriers. J. Neuropsychiatry Clin. Neurosci. 2007 , 19 , 441–448. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Van Duijn, E.; Craufurd, D.; Hubers, A.A.M.; Giltay, E.J.; Bonelli, R.; Rickards, H.; Anderson, K.E.; Van Walsem, M.R.; Van Der Mast, R.C.; Orth, M.; et al. Neuropsychiatric symptoms in a European Huntington’s disease cohort (REGISTRY). J. Neurol. Neurosurg. Psychiatry 2014 , 85 , 1411–1418. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Paulsen, J.S.; Ready, R.E.; Hamilton, J.M.; Mega, M.S.; Cummings, J.L. Neuropsychiatric aspects of Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 2001 , 71 , 310–314. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Moulton, C.D.; Hopkins, C.W.P.; Bevan-Jones, W.R. Systematic review of pharmacological treatments for depressive symptoms in Huntington’s disease. Mov. Disord. 2014 , 29 , 1556–1561. [ Google Scholar ] [ CrossRef ]
• Rosenblatt, A.; Ranen, N.G.; Nance, M.A.; Paulsen, J.S. A Physician’s Guide to the Management of Huntington Disease , 2nd ed.; Huntington Society of Canada: Waterloo, ON, Canada, 1999. [ Google Scholar ]
• Paleacu, D.; Anca, M.; Giladi, N. Olanzapine in Huntington’s disease. Acta Neurol. Scand. 2002 , 105 , 441–444. [ Google Scholar ] [ CrossRef ]
• Squitieri, F.; Cannella, M.; Porcellini, A.; Brusa, L.; Simonelli, M.; Ruggieri, S. Short-term effects of olanzapine in Huntington disease. Neuropsychiatry Neuropsychol. Behav. Neurol. 2001 , 14 , 69–72. [ Google Scholar ] [ PubMed ]
• Duff, K.; Beglinger, L.J.; O’Rourke, M.E.; Nopoulos, P.; Paulson, H.L.; Paulsen, J.S. Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington’s disease. Ann. Clin. Psychiatry 2008 , 20 , 1–3. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Sajatouic, M.; Verbanac, P.; Ramirez, L.F.; Meltzer, H.Y. Clozapine treatment of psychiatric symptoms resistant to neuroleptic treatment in patients with Huntington’s chorea. Neurology 1991 , 41 , 156. [ Google Scholar ] [ CrossRef ]
• Groves, M.; van Duijn, E.; Anderson, K.; Craufurd, D.; Edmondson, M.C.; Goodman, N.; van Kammen, D.P.; Goodman, L. An International Survey-based Algorithm for the Pharmacologic Treatment of Irritability in Huntington’s Disease. PLoS Curr. 2011 , 3 , RRN1259. [ Google Scholar ] [ CrossRef ]
• Anderson, K.; Craufurd, D.; Edmondson, M.C.; Goodman, N.; Groves, M.; van Duijn, E.; van Kammen, D.P.; Goodman, L.V. An International survey-based algorithm for the pharmacologic treatment of obsessive-compulsive behaviors in Huntington’s disease. PLoS Curr. 2011 , 3 , RRN1261. [ Google Scholar ] [ CrossRef ]
• Oosterloo, M.; Craufurd, D.; Nijsten, H.; Van Duijn, E. Obsessive-Compulsive and Perseverative Behaviors in Huntington’s Disease. J. Huntingtons. Dis. 2019 , 8 , 1–7. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Seitz, D.P.; Millson, R.C. Quetiapine in the Management of Psychosis Secondary to Huntington’s Disease: A Case Report. Can. J. Psychiatry 2004 , 49 , 413. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Alpay, M.; Koroshetz, W.J. Quetiapine in the treatment of behavioral disturbances in patients with Huntington’s disease. Psychosomatics 2006 , 47 , 70–72. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Uhlyar, S.; Rey, J.A. Valbenazine (Ingrezza): The first FDA-approved treatment for tardive dyskinesia. Pharm. Ther. 2018 , 43 , 328–331. [ Google Scholar ]
• Leysen, J.E.; Janssen, P.M.F.; Megens, A.A.H.P.; Schotte, A. Risperidone: A novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J. Clin. Psychiatry 1994 , 55 , 5–12. [ Google Scholar ]
• Taylor, C.P.; Traynelis, S.F.; Siffert, J.; Pope, L.E.; Matsumoto, R.R. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta ® ) clinical use. Pharmacol. Ther. 2016 , 164 , 170–182. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Amin, L.; Le, N.; Mercer, R.C.C.; Germann, U.; Alam, J.; Harris, D.A. Role of P38α MAP kinase in amyloid-β derived diffusible ligand (ADDL) induced dendritic spine loss in hippocampal neurons. Alzheimers Dement. 2019 , 15 , P1507. [ Google Scholar ] [ CrossRef ]
• Jiang, Y.; Stavrides, P.; Darji, S.; Yang, D.-S.; Bleiwas, C.; Smiley, J.; Germann, U.; Alam, J.; Nixon, R. Effects of P38α MAP kinase inhibition on the neurodegenerative phenotype of the TS2 Down Syndrome mouse model. Alzheimers Dement. 2019 , 15 , P1597. [ Google Scholar ] [ CrossRef ]
• Valero, T. Editorial (Thematic Issue: Mitochondrial Biogenesis: Pharmacological Approaches). Curr. Pharm. Des. 2014 , 20 , 5507–5509. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Adanyeguh, I.M.; Rinaldi, D.; Henry, P.G.; Caillet, S.; Valabregue, R.; Durr, A.; Mochel, F. Triheptanoin improves brain energy metabolism in patients with Huntington disease. Neurology 2015 , 84 , 490–495. [ Google Scholar ] [ CrossRef ]
• Vázquez-Manrique, R.P.; Farina, F.; Cambon, K.; Dolores Sequedo, M.; Parker, A.J.; Millán, J.M.; Weiss, A.; Déglon, N.; Neri, C. AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of huntington’s disease. Hum. Mol. Genet. 2015 , 25 , 1043–1058. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sanchis, A.; García-Gimeno, M.A.; Cañada-Martínez, A.J.; Sequedo, M.D.; Millán, J.M.; Sanz, P.; Vázquez-Manrique, R.P. Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease. Exp. Mol. Med. 2019 , 51 , 1–16. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ma, T.C.; Buescher, J.L.; Oatis, B.; Funk, J.A.; Nash, A.J.; Carrier, R.L.; Hoyt, K.R. Metformin therapy in a transgenic mouse model of Huntington’s disease. Neurosci. Lett. 2007 , 411 , 98–103. [ Google Scholar ] [ CrossRef ]
• Hervás, D.; Fornés-Ferrer, V.; Gómez-Escribano, A.P.; Sequedo, M.D.; Peiró, C.; Millán, J.M.; Vázquez-Manrique, R.P. Metformin intake associates with better cognitive function in patients with Huntington’s disease. PLoS ONE 2017 , 12 , 1–11. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Wang, J.Y.J. Regulation of cell death by the Abl tyrosine kinase. Oncogene 2000 , 19 , 5643–5650. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Ko, H.S.; Lee, Y.; Shin, J.H.; Karuppagounder, S.S.; Gadad, B.S.; Koleske, A.J.; Pletnikova, O.; Troncoso, J.C.; Dawson, V.L.; Dawson, T.M. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function. Proc. Natl. Acad. Sci. USA 2010 , 107 , 16691–16696. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Imam, S.Z.; Zhou, Q.; Yamamoto, A.; Valente, A.J.; Ali, S.F.; Bains, M.; Roberts, J.L.; Kahle, P.J.; Clark, R.A.; Li, S. Novel regulation of Parkin function through c-Abl-mediated tyrosine phosphorylation: Implications for Parkinson’s disease. J. Neurosci. 2011 , 31 , 157–163. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Kumar, M.J.V.; Shah, D.; Giridharan, M.; Yadav, N.; Manjithaya, R.; Clement, J.P. Spatiotemporal analysis of soluble aggregates and autophagy markers in the R6/2 mouse model. Sci. Rep. 2021 , 11 , 1–20. [ Google Scholar ] [ CrossRef ]
• Meng, L.; Zhao, P.; Hu, Z.; Ma, W.; Niu, Y.; Su, J.; Zhang, Y.; Nilotinib, A. Tyrosine Kinase Inhibitor, Suppresses the Cell Growth and Triggers Autophagy in Papillary Thyroid Cancer. Anticancer Agents Med. Chem. 2021 , 21 . [ Google Scholar ] [ CrossRef ]
• Yu, H.C.; Lin, C.S.; Tai, W.T.; Liu, C.Y.; Shiau, C.W.; Chen, K.F. Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation. J. Biol. Chem. 2013 , 288 , 18249–18259. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Lonskaya, I.; Hebron, M.L.; Desforges, N.M.; Schachter, J.B.; Moussa, C.E.H. Nilotinib-induced autophagic changes increase endogenous parkin level and ubiquitination, leading to amyloid clearance. J. Mol. Med. 2014 , 92 , 373–386. [ Google Scholar ] [ CrossRef ]
• Prerna, K.; Dubey, V.K. Repurposing of FDA-approved drugs as autophagy inhibitors in tumor cells. J. Biomol. Struct. Dyn. 2021 , 1–12. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Pagan, F.; Hebron, M.; Valadez, E.H.; Torres-Yaghi, Y.; Huang, X.; Mills, R.R.; Wilmarth, B.M.; Howard, H.; Dunn, C.; Carlson, A.; et al. Nilotinib effects in Parkinson’s disease and dementia with lewy bodies. J. Parkinson’s Dis. 2016 , 6 , 503–517. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Hebron, M.L.; Lonskaya, I.; Moussa, C.E.H. Nilotinib reverses loss of dopamine neurons and improvesmotorbehavior via autophagic degradation of α-synuclein in parkinson’s disease models. Hum. Mol. Genet. 2013 , 22 , 3315–3328. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Corrochano, S.; Renna, M.; Carter, S.; Chrobot, N.; Kent, R.; Stewart, M.; Cooper, J.; Brown, S.D.M.; Rubinsztein, D.C.; Acevedo-Arozena, A. α-Synuclein levels modulate Huntington’s disease in mice. Hum. Mol. Genet. 2012 , 21 , 485–494. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Lansita, J.A.; Mease, K.M.; Qiu, H.; Yednock, T.; Sankaranarayanan, S.; Kramer, S. Nonclinical Development of ANX005: A Humanized Anti-C1q Antibody for Treatment of Autoimmune and Neurodegenerative Diseases. Int. J. Toxicol. 2017 , 36 , 449–462. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Carpanini, S.M.; Torvell, M.; Morgan, B.P. Therapeutic Inhibition of the Complement System in Diseases of the Central Nervous System. Front. Immunol. 2019 , 10 , 1–17. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mestre, T.A. Recent advances in the therapeutic development for Huntington disease. Park. Relat. Disord. 2019 , 59 , 125–130. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Tabrizi, S.J.; Leavitt, B.R.; Landwehrmeyer, G.B.; Wild, E.J.; Saft, C.; Barker, R.A.; Blair, N.F.; Craufurd, D.; Priller, J.; Rickards, H.; et al. Targeting Huntingtin Expression in Patients with Huntington’s Disease. N. Engl. J. Med. 2019 , 380 , 2307–2316. [ Google Scholar ] [ CrossRef ]
• Evers, M.M.; Miniarikova, J.; Juhas, S.; Vallès, A.; Bohuslavova, B.; Juhasova, J.; Skalnikova, H.K.; Vodicka, P.; Valekova, I.; Brouwers, C. AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington’s Disease Minipig Model. Mol. Ther. 2018 , 26 , 2163–2177. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Spronck, E.A.; Brouwers, C.C.; Vallès, A.; Haan, M.; Petry, H.; Van Deventer, S.J.; Konstantinova, P.; Evers, M.M. AAV5-miHTT Gene Therapy Demonstrates Sustained Huntingtin Lowering and Functional Improvement in Huntington Disease Mouse Models. Mol. Ther. Methods Clin. Dev. 2019 , 13 , 334–343. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Miniarikova, J.; Zimmer, V.; Martier, R.; Brouwers, C.C.; Pythoud, C.; Richetin, K.; Rey, M.; Lubelski, J.; Evers, M.M.; Van Deventer, S.J. AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington’s disease. Gene Ther. 2017 , 24 , 630–639. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Caron, N.S.; Southwell, A.L.; Brouwers, C.C.; Cengio, L.D.; Xie, Y.; Black, H.F.; Anderson, L.M.; Ko, S.; Zhu, X.; van Deventer, S.J. Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease. Nucleic Acids Res. 2019 , 48 , 36–54. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Keskin, S.; Brouwers, C.C.; Sogorb-Gonzalez, M.; Martier, R.; Depla, J.A.; Vallès, A.; van Deventer, S.J.; Konstantinova, P.; Evers, M.M. AAV5-miHTT lowers huntingtin mRNA and protein without Off-Target effects in patient-derived neuronal cultures and astrocytes. Mol. Ther. Methods Clin. Dev. 2019 , 15 , 275–284. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Spronck, E.A.; Vallès, A.; Lampen, M.H.; Montenegro-Miranda, P.S.; Keskin, S.; Heijink, L.; Evers, M.M.; Petry, H.; Deventer, S.; Konstantinova, P.; et al. Intrastriatal Administration of AAV5-miHTT in non-human primates and rats is well tolerated and results in miHTT transgene expression in key areas of Huntington disease pathology. Brain Sci. 2021 , 11 , 129. [ Google Scholar ] [ CrossRef ]
• Wadman, M. Promising drug for Huntington disease fails in major trial. Science 2021 . [ Google Scholar ] [ CrossRef ]
• Claustrat, B.; Leston, J. Melatonin: Physiological effects in humans. Neurochirurgie 2015 , 61 , 77–84. [ Google Scholar ] [ CrossRef ]
• Zhang, P.Y.; Liu, X.J.; Zhang, Y.Q. Biotin-thiamine-responsive basal ganglia disease. Chinese J. Pediatr. 2018 , 56 , 462–464. [ Google Scholar ] [ CrossRef ]
• Ranen, N.G.; Peyser, C.E.; Coyle, J.T.; Bylsma, F.W.; Sherr, M.; Day, L.; Folstein, M.F.; Brandt, J.; Ross, C.A.; Folstein, S.E. A controlled trial of idebenone in Huntington’s disease. Mov. Disord. 1996 , 11 , 549–554. [ Google Scholar ] [ CrossRef ]
• Wenceslau, C.V.; Kerkis, I.; Pompeia, C.; Haddad, M.S. Pluripotent Stem Cells to Model and Treat Huntington’s Disease. In Huntington’s Disease—Molecular Pathogenesis and Current Models ; InTech: Palm Beach, FL, USA, 2017. [ Google Scholar ]
• Mu, S.; Wang, J.; Zhou, G.; Peng, W.; He, Z.; Zhao, Z.; Mo, C.P.; Qu, J.; Zhang, J. Transplantation of induced pluripotent stem cells improves functional recovery in Huntington’s disease rat model. PLoS ONE 2014 , 9 , 101185. [ Google Scholar ] [ CrossRef ]
• Benabid, A.L.; Pollak, P.; Louveau, A.; Henry, S.; De Rougemont, J. Combined (thalamotomy and stimulation) stereotactic surgery of the vim thalamic nucleus for bilateral parkinson disease. Stereotact. Funct. Neurosurg. 1987 , 50 , 344–346. [ Google Scholar ] [ CrossRef ]
• Watson Alberts, W.; Wright, E.W.; Levin, G.; Feinstein, B.; Mueller, M. Threshold stimulation of the lateral thalamus and globus pallidus in the waking human. Electroencephalogr. Clin. Neurophysiol. 1961 , 13 , 68–74. [ Google Scholar ] [ CrossRef ]
• Sem-Jacobsen, C.W. Depth-electrographic observations related to Parkinson’s disease. Recording and electrical stimulation in the area around the third ventricle. J. Neurosurg. 1966 , 24 , 388–402. [ Google Scholar ]
• Mundinger, F. New stereotactic treatment of spasmodic torticollis with a brain stimulation system. Med. Klin. 1977 , 72 , 1982–1986. [ Google Scholar ]
• Herrington, T.M.; Cheng, J.J.; Eskandar, E.N. Mechanisms of deep brain stimulation. J. Neurophysiol. 2016 , 115 , 19–38. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Fasano, A.; Mazzone, P.; Piano, C.; Quaranta, D.; Soleti, F.; Bentivoglio, A.R. GPi-DBS in Huntington’s disease: Results on motor function and cognition in a 72-year-old case. Mov. Disord. 2008 , 23 , 1289–1292. [ Google Scholar ] [ CrossRef ]
• Moro, E.; Lang, A.E.; Strafella, A.P.; Poon, Y.Y.W.; Arango, P.M.; Dagher, A.; Hutchison, W.D.; Lozano, A.M. Bilateral globus pallidus stimulation for Huntington’s disease. Ann. Neurol. 2004 , 56 , 290–294. [ Google Scholar ] [ CrossRef ]
• Gonzalez, V.; Cif, L.; Biolsi, B.; Garcia-Ptacek, S.; Seychelles, A.; Sanrey, E.; Descours, I.; Coubes, C.; Ribeiro De Moura, A.M.; Corlobe, A.; et al. Deep brain stimulation for Huntington’s disease: Long-term results of a prospective open-label study: Clinical article. J. Neurosurg. 2014 , 121 , 114–122. [ Google Scholar ] [ CrossRef ]
• Gruber, D.; Kuhn, A.A.; Schoenecker, T.; Kopp, U.A.; Kivi, A.; Huebl, J.; Lobsien, E.; Mueller, B.; Schneider, G.H.; Kupsch, A. Quadruple deep brain stimulation in Huntington’s disease, targeting pallidum and subthalamic nucleus: Case report and review of the literature. J. Neural Transm. 2014 , 121 , 1303–1312. [ Google Scholar ] [ CrossRef ]
• Fawcett, A.P.; Moro, E.; Lang, A.E.; Lozano, A.M.; Hutchison, W.D. Pallidal deep brain stimulation influences both reflexive and voluntary saccades in Huntington’s disease. Mov. Disord. 2005 , 20 , 371–377. [ Google Scholar ] [ CrossRef ]
• Hebb, M.O.; Garcia, R.; Gaudet, P.; Mendez, I.M. Bilateral stimulation of the globus pallidus internus to treat choreathetosis in Huntington’s disease: Technical case report. Neurosurgery 2006 , 58 . [ Google Scholar ] [ CrossRef ]
• Garcia-Ruiz, P.J.; Ayerbe, J.; del Val, J.; Herranz, A. Deep brain stimulation in disabling involuntary vocalization associated with Huntington’s disease. Parkinsonism Relat. Disord. 2012 , 18 , 803–804. [ Google Scholar ] [ CrossRef ]
• Biolsi, B.; Cif, L.; El Fertit, H.; Robles, S.G.; Coubes, P. Long-term follow-up of Huntington disease treated by bilateral deep brain stimulation of the internal globus pallidus: Case report. J. Neurosurg. 2008 , 109 , 130–132. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Kang, G.A.; Heath, S.; Rothlind, J.; Starr, P.A. Long-term follow-up of pallidal deep brain stimulation in two cases of Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 2011 , 82 , 272–277. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Spielberger, S.; Hotter, A.; Wolf, E.; Eisner, W.; Müller, J.; Poewe, W.; Seppi, K. Deep brain stimulation in Huntington’s disease: A 4-year follow-up case report. Mov. Disord. 2012 , 27 , 806–807. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• López-Sendón Moreno, J.L.; García-Caldentey, J.; Regidor, I.; del Álamo, M.; García de Yébenes, J. A 5-year follow-up of deep brain stimulation in Huntington’s disease. Parkinsonism Relat. Disord. 2014 , 20 , 260–261. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Cislaghi, G.; Capiluppi, E.; Saleh, C.; Romano, L.; Servello, D.; Mariani, C.; Porta, M. Bilateral Globus Pallidus Stimulation in Westphal Variant of Huntington Disease. Neuromodulation Technol. Neural Interface 2014 , 17 , 502–505. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Khalil, H.; Quinn, L.; Van Deursen, R.; Dawes, H.; Playle, R.; Rosser, A.; Busse, M. What effect does a structured home-based exercise programme have on people with Huntington’s disease? A randomized, controlled pilot study. Clin. Rehabil. 2013 , 27 , 646–658. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Quinn, L.; Debono, K.; Dawes, H.; Rosser, A.E.; Nemeth, A.H.; Rickards, H.; Tabrizi, S.J.; Quarrell, O.; Trender-Gerhard, I.; Kelson, M.J.; et al. Task-specific training in Huntington disease: A randomized controlled feasibility trial. Phys. Ther. 2014 , 94 , 1555–1568. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Quinn, L.; Hamana, K.; Kelson, M.; Dawes, H.; Collett, J.; Townson, J.; Roos, R.; van der Plas, A.A.; Reilmann, R.; Frich, J.C.; et al. A randomized, controlled trial of a multi-modal exercise intervention in Huntington’s disease. Park. Relat. Disord. 2016 , 31 , 46–52. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Busse, M.; Quinn, L.; Debono, K.; Jones, K.; Collett, J.; Playle, R.; Kelly, M.; Simpson, S.; Backx, K.; Wasley, D.; et al. A randomized feasibility study of a 12-week community-based exercise program for people with Huntington’s disease. J. Neurol. Phys. Ther. 2013 , 37 , 149–158. [ Google Scholar ] [ CrossRef ]
• Kloos, A.D.; Fritz, N.E.; Kostyk, S.K.; Young, G.S.; Kegelmeyer, D.A. Video game play (Dance Dance Revolution) as a potential exercise therapy in Huntington’s disease: A controlled clinical trial. Clin. Rehabil. 2013 , 27 , 972–982. [ Google Scholar ] [ CrossRef ]
• Fritz, N.; Rao, A.K.; Kegelmeyer, D.; Kloos, A.; Busse, M.; Hartel, L.; Carrier, J.; Quinn, L. Physical Therapy and Exercise Interventions in Huntington’s Disease: A Mixed Methods Systematic Review. J. Huntingtons. Dis. 2017 , 6 , 217–236. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Drew, C.J.G.; Quinn, L.; Hamana, K.; Williams-Thomas, R.; Marsh, L.; Dimitropoulou, P.; Playle, R.; Griffin, B.A.; Kelson, M.; Schubert, R.; et al. Physical Activity and Exercise Outcomes in Huntington Disease (PACE-HD): Protocol for a 12-Month Trial Within Cohort Evaluation of a Physical Activity Intervention in People with Huntington Disease. Phys. Ther. 2019 , 99 , 1201–1210. [ Google Scholar ] [ CrossRef ]
• Zuccato, C.; Cattaneo, E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol. 2009 , 5 , 311–322. [ Google Scholar ] [ CrossRef ]
• Elifani, F.; Amico, E.; Pepe, G.; Capocci, L.; Castaldo, S.; Rosa, P.; Montano, E.; Pollice, A.; Madonna, M.; Filosa, S.; et al. Curcumin dietary supplementation ameliorates disease phenotype in an animal model of Huntington’s disease. Hum. Mol. Genet. 2019 , 28 , 4012–4021. [ Google Scholar ] [ CrossRef ]
• Spires, T.L.; Grote, H.E.; Varshney, N.K.; Cordery, P.M.; Van Dellen, A.; Blakemore, C.; Hannan, A.J. Environmental Enrichment Rescues Protein Deficits in a Mouse Model of Huntington’s Disease, Indicating a Possible Disease Mechanism. J. Neurosci. 2004 , 24 , 2270–2276. [ Google Scholar ] [ CrossRef ]
• Couly, S.; Carles, A.; Denus, M.; Benigno-Anton, L.; Maschat, F.; Maurice, T. Exposure of R6/2 mice in an enriched environment augments P42 therapy efficacy on Huntington’s disease progression. Neuropharmacology 2021 , 186 , 108467. [ Google Scholar ] [ CrossRef ]
• Kim, Y.-M.; Ji, E.-S.; Kim, S.-H.; Kim, T.-W.; Ko, I.-G.; Jin, J.-J.; Kim, C.-J.; Kim, T.-W.; Kim, D.-H. Treadmill exercise improves short-term memory by enhancing hippocampal cell proliferation in quinolinic acid-induced Huntington’s disease rats. J. Exerc. Rehabil. 2015 , 11 , 5–11. [ Google Scholar ] [ CrossRef ]
• Zajac, M.S.; Pang, T.Y.C.; Wong, N.; Weinrich, B.; Leang, L.S.K.; Craig, J.M.; Saffery, R.; Hannan, A.J. Wheel running and environmental enrichment differentially modify exon-specific BDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntington’s disease mice. Hippocampus 2010 , 20 , 621–636. [ Google Scholar ] [ CrossRef ]
• Canals, J.M.; Pineda, J.R.; Torres-Peraza, J.F.; Bosch, M.; Martín-Ibañez, R.; Muñoz, M.T.; Mengod, G.; Ernfors, P.; Alberch, J. Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J. Neurosci. 2004 , 24 , 7727–7739. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Cho, S.R.; Benraiss, A.; Chmielnicki, E.; Samdani, A.; Economides, A.; Goldman, S.A. Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J. Clin. Investig. 2007 , 117 , 2889–2902. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kells, A.P.; Fong, D.M.; Dragunow, M.; During, M.J.; Young, D.; Connor, B. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol. Ther. 2004 , 9 , 682–688. [ Google Scholar ] [ CrossRef ]
• Frim, D.M.; Uhler, T.A.; Short, M.P.; Ezzedine, Z.D.; Klagsbrun, M.; Breakefield, X.O.; Isacson, O. Effects of biologically delivered NGF, bdnf and BFGF on striatal excitotoxic lesions. Neuroreport 1993 , 4 , 367–370. [ Google Scholar ] [ CrossRef ]
• Martínez-Serrano, A.; Björklund, A. Protection of the neostriatum against excitotoxic damage by neurotrophin-producing, genetically modified neural stem cells. J. Neurosci. 1996 , 16 , 4604–4616. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Pérez-Navarro, E.; Alberch, J.; Neveu, I.; Arenas, E. Brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 differentially regulate the phenotype and prevent degenerative changes in striatal projection neurons after excitotoxicity in vivo. Neuroscience 1999 , 91 , 1257–1264. [ Google Scholar ] [ CrossRef ]
• Pérez-Navarro, E.; Canudas, A.A.; Akerud, P.; Alberch, J.; Arenas, E. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 prevent the death of striatal projection neurons in a rodent model of Huntington’s disease. J. Neurochem. 2000 , 75 , 2190–2199. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ryu, J.K.; Kim, J.; Cho, S.J.; Hatori, K.; Nagai, A.; Choi, H.B.; Lee, M.C.; McLarnon, J.G.; Kim, S.U. Proactive transplantation of human neural stem cells prevents degeneration of striatal neurons in a rat model of Huntington disease. Neurobiol. Dis. 2004 , 16 , 68–77. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sari, Y. Potential Drugs and Methods for Preventing or Delaying the Progression of Huntington’s Disease. Recent Pat. CNS Drug Discov. 2011 , 6 , 80–90. [ Google Scholar ] [ CrossRef ]
• Gill, S.S.; Patel, N.K.; Hotton, G.R.; O’Sullivan, K.; McCarter, R.; Bunnage, M.; Brooks, D.J.; Svendsen, C.N.; Heywood, P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 2003 , 9 , 589–595. [ Google Scholar ] [ CrossRef ]
• Arregui, L.; Benítez, J.A.; Razgado, L.F.; Vergara, P.; Segovia, J. Adenoviral astrocyte-specific expression of BDNF in the striata of mice transgenic for Huntington’s disease delays the onset of the motor phenotype. Cell. Mol. Neurobiol. 2011 , 31 , 1229–1243. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Teng, H.K.; Teng, K.K.; Lee, R.; Wright, S.; Tevar, S.; Almeida, R.D.; Kermani, P.; Torkin, R.; Chen, Z.Y.; Lee, F.S.; et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 2005 , 25 , 5455–5463. [ Google Scholar ] [ CrossRef ]
• Hacein-Bey-Abina, S.; Garrigue, A.; Wang, G.P.; Soulier, J.; Lim, A.; Morillon, E.; Clappier, E.; Caccavelli, L.; Delabesse, E.; Beldjord, K.; et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Investig. 2008 , 118 , 3132–3142. [ Google Scholar ] [ CrossRef ]
• Biffi, A.; Naldini, L. Gene therapy of storage disorders by retroviral and lentiviral vectors. Hum. Gene Ther. 2005 , 16 , 1133–1142. [ Google Scholar ] [ CrossRef ]
• Yáñez-Muñoz, R.J.; Balaggan, K.S.; MacNeil, A.; Howe, S.J.; Schmidt, M.; Smith, A.J.; Buch, P.; MacLaren, R.E.; Anderson, P.N.; Barker, S.E.; et al. Effective gene therapy with nonintegrating lentiviral vectors. Nat. Med. 2006 , 12 , 348–353. [ Google Scholar ] [ CrossRef ]
• Conti, L.; Cattaneo, E. Neural stem cell systems: Physiological players or in vitro entities? Nat. Rev. Neurosci. 2010 , 11 , 176–187. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Rossi, F.; Cattaneo, E. Neural stem cell therapy for neurological diseases: Dreams and reality. Nat. Rev. Neurosci. 2002 , 3 , 401–409. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Schiefer, J.; Landwehrmeyer, G.B.; Lüesse, H.G.; Sprünken, A.; Puls, C.; Milkereit, A.; Milkereit, E.; Kosinski, C.M. Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington’s disease. Mov. Disord. 2002 , 17 , 748–757. [ Google Scholar ] [ CrossRef ]
• Hockly, E.; Tse, J.; Barker, A.L.; Moolman, D.L.; Beunard, J.L.; Revington, A.P.; Holt, K.; Sunshine, S.; Moffitt, H.; Sathasivam, K.; et al. Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington’s disease. Neurobiol. Dis. 2006 , 21 , 228–236. [ Google Scholar ] [ CrossRef ]
• Lesort, M.; Lee, M.; Tucholski, J.; Johnson, G.V.W. Cystamine inhibits caspase activity: Implications for the treatment of polyglutamine disorders. J. Biol. Chem. 2003 , 278 , 3825–3830. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Fox, J.H.; Barber, D.S.; Singh, B.; Zucker, B.; Swindell, M.K.; Norflus, F.; Buzescu, R.; Chopra, R.; Ferrante, R.J.; Kazantsev, A.; et al. Cystamine increases L-cysteine levels in Huntington’s disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation. J. Neurochem. 2004 , 91 , 413–422. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Borrell-Pagès, M.; Canals, J.M.; Cordelières, F.P.; Parker, J.A.; Pineda, J.R.; Grange, G.; Bryson, E.A.; Guillermier, M.; Hirsch, E.; Hantraye, P.; et al. Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J. Clin. Investig. 2006 , 116 , 1410–1424. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Powrozek, T.; Sari, Y.; Singh, R.; Zhou, F. Neurotransmitters and Substances of Abuse: Effects on Adult Neurogenesis. Curr. Neurovasc. Res. 2005 , 1 , 251–260. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Gewirtz, J.C.; Chen, A.C.; Terwilliger, R.; Duman, R.C.; Marek, G.J. Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. Pharmacol. Biochem. Behav. 2002 , 73 , 317–326. [ Google Scholar ] [ CrossRef ]
• Vaidya, V.A.; Marek, G.J.; Aghajanian, G.K.; Duman, R.S. 5-HT(2A) receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J. Neurosci. 1997 , 17 , 2785–2795. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Vaidya, V.A.; Terwilliger, R.M.Z.; Duman, R.S. Role of 5-HT(2a) receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci. Lett. 1999 , 262 , 1–4. [ Google Scholar ] [ CrossRef ]
• Duman, R.S. Novel therapeutic approaches beyond the serotonin receptor. Biol. Psychiatry 1998 , 44 , 324–335. [ Google Scholar ] [ CrossRef ]
• Duan, W.; Guo, Z.; Jiang, H.; Ladenheim, B.; Xu, X.; Cadet, J.L.; Mattson, M.P. Paroxetine Retards Disease Onset and Progression in Huntingtin Mutant Mice. Ann. Neurol. 2004 , 55 , 590–594. [ Google Scholar ] [ CrossRef ]
• Grote, H.E.; Bull, N.D.; Howard, M.L.; Van Dellen, A.; Blakemore, C.; Bartlett, P.F.; Hannan, A.J. Cognitive disorders and neurogenesis deficits in Huntington’s disease mice are rescued by fluoxetine. Eur. J. Neurosci. 2005 , 22 , 2081–2088. [ Google Scholar ] [ CrossRef ]
• Duan, W.; Peng, Q.; Masuda, N.; Ford, E.; Tryggestad, E.; Ladenheim, B.; Zhao, M.; Cadet, J.L.; Wong, J.; Ross, C.A. Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington’s disease. Neurobiol. Dis. 2008 , 30 , 312–322. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Slaughter, J.R.; Martens, M.P.; Slaughter, K.A. Depression and Huntington’s disease: Prevalence, clinical manifestations, etiology, and treatment. CNS Spectr. 2001 , 6 , 306–326. [ Google Scholar ] [ CrossRef ]
• Cong, W.N.; Chadwick, W.; Wang, R.; Daimon, C.M.; Cai, H.; Amma, J.; Wood, W.H.; Becker, K.G.; Martin, B.; Maudsley, S. Amitriptyline improves motor function via enhanced neurotrophin signaling and mitochondrial functions in the murine N171-82Q Huntington disease model. J. Biol. Chem. 2015 , 290 , 2728–2743. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Ellrichmann, G.; Blusch, A.; Fatoba, O.; Brunner, J.; Hayardeny, L.; Hayden, M.; Sehr, D.; Winklhofer, K.F.; Saft, C.; Gold, R. Laquinimod treatment in the R6/2 mouse model. Sci. Rep. 2017 , 7 . [ Google Scholar ] [ CrossRef ]
• Garcia-Miralles, M.; Yusof, N.A.B.M.; Tan, J.Y.; Radulescu, C.I.; Sidik, H.; Tan, L.J.; Belinson, H.; Zach, N.; Hayden, M.R.; Pouladi, M.A. Laquinimod Treatment Improves Myelination Deficits at the Transcriptional and Ultrastructural Levels in the YAC128 Mouse Model of Huntington Disease. Mol. Neurobiol. 2019 , 56 , 4464–4478. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Corey-Bloom, J.; Aikin, A.M.; Gutierrez, A.M.; Nadhem, J.S.; Howell, T.L.; Thomas, E.A. Beneficial effects of glatiramer acetate in Huntington’s disease mouse models: Evidence for BDNF-elevating and immunomodulatory mechanisms. Brain Res. 2017 , 1673 , 102–110. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Reick, C.; Ellrichmann, G.; Tsai, T.; Lee, D.H.; Wiese, S.; Gold, R.; Saft, C.; Linker, R.A. Expression of brain-derived neurotrophic factor in astrocytes—Beneficial effects of glatiramer acetate in the R6/2 and YAC128 mouse models of Huntington’s disease. Exp. Neurol. 2016 , 285 , 12–23. [ Google Scholar ] [ CrossRef ]
• Anglada-Huguet, M.; Vidal-Sancho, L.; Giralt, A.; García-Díaz Barriga, G.; Xifró, X.; Alberch, J. Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington’s disease by the induction of BDNF-dependent synaptic plasticity. Neurobiol. Dis. 2016 , 95 , 22–34. [ Google Scholar ] [ CrossRef ]
• Da Fonsêca, V.S.; da Silva Colla, A.R.; de Paula Nascimento-Castro, C.; Plácido, E.; Rosa, J.M.; Farina, M.; Gil-Mohapel, J.; Rodrigues, A.L.S.; Brocardo, P.S. Brain-Derived Neurotrophic Factor Prevents Depressive-Like Behaviors in Early-Symptomatic YAC128 Huntington’s Disease Mice. Mol. Neurobiol. 2018 , 55 , 7201–7215. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Cheng, S.; Tereshchenko, J.; Zimmer, V.; Vachey, G.; Pythoud, C.; Rey, M.; Liefhebber, J.; Raina, A.; Streit, F.; Mazur, A.; et al. Therapeutic efficacy of regulable GDNF expression for Huntington’s and Parkinson’s disease by a high-induction, background-free “GeneSwitch” vector. Exp. Neurol. 2018 , 309 , 79–90. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Cabezas-Llobet, N.; Vidal-Sancho, L.; Masana, M.; Fournier, A.; Alberch, J.; Vaudry, D.; Xifró, X. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington’s Disease. Mol. Neurobiol. 2018 , 55 , 8263–8277. [ Google Scholar ] [ CrossRef ]
• Fatoba, O.; Kloster, E.; Reick, C.; Saft, C.; Gold, R.; Epplen, J.T.; Arning, L.; Ellrichmann, G. Activation of NPY-Y2 receptors ameliorates disease pathology in the R6/2 mouse and PC12 cell models of Huntington’s disease. Exp. Neurol. 2018 , 302 , 112–128. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Allen, S.J.; Watson, J.J.; Shoemark, D.K.; Barua, N.U.; Patel, N.K. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 2013 , 138 , 155–175. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Mandel, R.J.; Spratt, S.K.; Snyder, R.O.; Leff, S.E. Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson’s disease in rats. Proc. Natl. Acad. Sci. USA 1997 , 94 , 14083–14088. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Rahimi-Movaghar, V.; Yan, H.Q.; Li, Y.; Ma, X.; Akbarian, F.; Dixon, C.E. Increased expression of glial cell line-derived neurotrophic factor in rat brain after traumatic brain injury. Acta Med. Iran. 2005 , 43 , 7–10. [ Google Scholar ]
• Araujo, D.M.; Hilt, D.C. Glial cell line-derived neurotrophic factor attenuates the excitotoxin- induced behavioral and neurochemical deficits in a rodent model of Huntington’s disease. Neuroscience 1997 , 81 , 1099–1110. [ Google Scholar ] [ CrossRef ]
• McBride, J.L.; During, M.J.; Wuu, J.; Chen, E.Y.; Leurgans, S.E.; Kordower, J.H. Structural and functional neuroprotection in a rat model of Huntington’s disease by viral gene transfer of GDNF. Exp. Neurol. 2003 , 181 , 213–223. [ Google Scholar ] [ CrossRef ]
• McBride, J.L.; Ramaswamy, S.; Gasmi, M.; Bartus, R.T.; Herzog, C.D.; Brandon, E.P.; Zhou, L.; Pitzer, M.R.; Berry-Kravis, E.M.; Kordower, J.H. Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease. Proc. Natl. Acad. Sci. USA 2006 , 103 , 9345–9350. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Popovic, N.; Maingay, M.; Kirik, D.; Brundin, P. Lentiviral gene delivery of GDNF into the striatum of R6/2 Huntington mice fails to attenuate behavioral and neuropathological changes. Exp. Neurol. 2005 , 193 , 65–74. [ Google Scholar ] [ CrossRef ]
• Skaper, S.D.; Selak, I.; Manthorpe, M.; Varon, S. Chemically defined requirements for the survival of cultured 8-day chick embryo ciliary ganglion neurons. Brain Res. 1984 , 302 , 281–290. [ Google Scholar ] [ CrossRef ]
• Pasquin, S.; Sharma, M.; Gauchat, J.F. Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies. Cytokine Growth Factor Rev. 2015 , 26 , 507–515. [ Google Scholar ] [ CrossRef ]
• Anderson, K.D.; Panayotatos, N.; Corcoran, T.L.; Lindsay, R.M.; Wiegand, S.J. Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease. Proc. Natl. Acad. Sci. USA 1996 , 93 , 7346–7351. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Emerich, D.F.; Winn, S.R.; Hantraye, P.M.; Peschanski, M.; Chen, E.Y.; Chu, Y.; McDermott, P.; Baetge, E.E.; Kordower, J.H. Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 1997 , 386 , 395–399. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• De Almeida, L.P.; Zala, D.; Aebischer, P.; Déglon, N. Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington’s disease. Neurobiol. Dis. 2001 , 8 , 433–446. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Ramirez, B.U.; Retamal, L.; Vergara, C. Ciliary neurotrophic factor (CNTF) affects the excitable and contractile properties of innervated skeletal muscles. Biol. Res. 2003 , 36 , 303–312. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Bongioanni, P.; Reali, C.; Sogos, V. Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst. Rev. 2004 , 3 . [ Google Scholar ] [ CrossRef ]
• Boucher, J.; Tseng, Y.H.; Kahn, C.R. Insulin and insulin-like growth factor-1 receptors act as ligand-specific amplitude modulators of a common pathway regulating gene transcription. J. Biol. Chem. 2010 , 285 , 17235–17245. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Duarte, A.I.; Petit, G.H.; Ranganathan, S.; Li, J.Y.; Oliveira, C.R.; Brundin, P.; Björkqvist, M.; Rego, A.C. IGF-1 protects against diabetic features in an in vivo model of Huntington’s disease. Exp. Neurol. 2011 , 231 , 314–319. [ Google Scholar ] [ CrossRef ]
• Lopes, C.; Ribeiro, M.; Duarte, A.I.; Humbert, S.; Saudou, F.; Pereira De Almeida, L.; Hayden, M.; Rego, A.C. IGF-1 intranasal administration rescues Huntington’s disease phenotypes in YAC128 mice. Mol. Neurobiol. 2014 , 49 , 1126–1142. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• McCloskey, D.P.; Hintz, T.M.; Scharfman, H.E. Modulation of vascular endothelial growth factor (VEGF) expression in motor neurons and its electrophysiological effects. Brain Res. Bull. 2008 , 76 , 36–44. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Ellison, S.M.; Trabalza, A.; Tisato, V.; Pazarentzos, E.; Lee, S.; Papadaki, V.; Goniotaki, D.; Morgan, S.; Mirzaei, N.; Mazarakis, N.D. Dose-dependent neuroprotection of VEGF165 in Huntington’s disease striatum. Mol. Ther. 2013 , 21 , 1862–1875. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Ji, C.H.; Kwon, Y.T. Crosstalk and Interplay between the Ubiquitin-Proteasome System and Autophagy. Mol. Cells 2017 , 40 , 441–449. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Pohl, C.; Dikic, I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science 2019 , 366 , 818–822. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Wang, Y.; Le, W.-D. Autophagy and Ubiquitin-Proteasome System. In Advances in Experimental Medicine and Biology ; Springer: Berlin/Heidelberg, Germany, 2019; Volume 1206, pp. 527–550. [ Google Scholar ]
• Şentürk, M.; Lin, G.; Zuo, Z.; Mao, D.; Watson, E.; Mikos, A.G.; Bellen, H.J. Ubiquilins regulate autophagic flux through mTOR signalling and lysosomal acidification. Nat. Cell Biol. 2019 , 21 , 384–396. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Safren, N.; El Ayadi, A.; Chang, L.; Terrillion, C.E.; Gould, T.D.; Boehning, D.F.; Monteiro, M.J. Ubiquilin-1 overexpression increases the lifespan and delays accumulation of huntingtin aggregates in the R6/2 mouse model of huntington’s disease. PLoS ONE 2014 , 9 , e87513. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Weber, J.J.; Pereira Sena, P.; Singer, E.; Nguyen, H.P. Killing Two Angry Birds with One Stone: Autophagy Activation by Inhibiting Calpains in Neurodegenerative Diseases and Beyond. Biomed. Res. Int. 2019 , 2019 , 1–13. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Menzies, F.M.; Garcia-Arencibia, M.; Imarisio, S.; O’Sullivan, N.C.; Ricketts, T.; Kent, B.A.; Rao, M.V.; Lam, W.; Green-Thompson, Z.W.; Nixon, R.A.; et al. Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity. Cell Death Differ. 2015 , 22 , 433–444. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Cortes, C.J.; La Spada, A.R. TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: Molecular mechanisms, cellular processes, and emerging therapeutic opportunities. Neurobiol. Dis. 2019 , 122 , 83–93. [ Google Scholar ] [ CrossRef ]
• Vodicka, P.; Chase, K.; Iuliano, M.; Tousley, A.; Valentine, D.T.; Sapp, E.; Kegel-Gleason, K.B.; Sena-Esteves, M.; Aronin, N.; Difiglia, M. Autophagy Activation by Transcription Factor EB (TFEB) in Striatum of HD Q175/Q7 Mice. J. Huntingtons. Dis. 2016 , 5 , 249–260. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Lee, H.-J.; Yoon, Y.-S.; Lee, S.-J. Mechanism of neuroprotection by trehalose: Controversy surrounding autophagy induction. Cell Death Dis. 2018 , 9 , 712. [ Google Scholar ] [ CrossRef ]
• Tanaka, M.; Machida, Y.; Niu, S.; Ikeda, T.; Jana, N.R.; Doi, H.; Kurosawa, M.; Nekooki, M.; Nukina, N. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat. Med. 2004 , 10 , 148–154. [ Google Scholar ] [ CrossRef ]
• Rose, C.; Menzies, F.M.; Renna, M.; Acevedo-Arozena, A.; Corrochano, S.; Sadiq, O.; Brown, S.D.; Rubinsztein, D.C. Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum. Mol. Genet. 2010 , 19 , 2144–2153. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Underwood, B.R.; Green-Thompson, Z.W.; Pugh, P.J.; Lazic, S.E.; Mason, S.L.; Griffin, J.; Jones, P.S.; Rowe, J.B.; Rubinsztein, D.C.; Barker, R.A. An open-label study to assess the feasibility and tolerability of rilmenidine for the treatment of Huntington’s disease. J. Neurol. 2017 , 264 , 2457–2463. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Jiang, W.; Wei, W.; Gaertig, M.A.; Li, S.; Li, X.J. Therapeutic effect of berberine on Huntington’s disease transgenic mouse model. PLoS ONE 2015 , 10 , e0134142. [ Google Scholar ] [ CrossRef ]
• Zhang, T.; Dong, K.; Liang, W.; Xu, D.; Xia, H.; Geng, J.; Najafov, A.; Liu, M.; Li, Y.; Han, X.; et al. G-protein Coupled Receptors Regulate Autophagy by ZBTB16-mediated Ubiquitination and Proteasomal Degradation of Adaptor Protein Atg14L. Elife 2015 , 2015 , e06734. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Jeon, J.; Kim, W.; Jang, J.; Isacson, O.; Seo, H. Gene therapy by proteasome activator, PA28γ, improves motor coordination and proteasome function in Huntington’s disease YAC128 mice. Neuroscience 2016 , 324 , 20–28. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Valionyte, E.; Yang, Y.; Roberts, S.L.; Kelly, J.; Lu, B.; Luo, S. Lowering Mutant Huntingtin Levels and Toxicity: Autophagy-Endolysosome Pathways in Huntington’s Disease. J. Mol. Biol. 2020 , 432 , 2673–2691. [ Google Scholar ] [ CrossRef ]
• Neo, S.H.; Tang, B.L. Sirtuins as Modifiers of Huntington’s Disease (HD) Pathology. In Progress in Molecular Biology and Translational Science ; Elsevier B.V.: Amsterdam, The Netherlands, 2018; Volume 154, pp. 105–145. [ Google Scholar ]
• Duan, W. Targeting Sirtuin-1 in Huntington’s Disease: Rationale and Current Status. CNS Drugs 2013 , 27 , 345–352. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Lee, I.H. Mechanisms and disease implications of sirtuin-mediated autophagic regulation. Exp. Mol. Med. 2019 , 51 , 1–11. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Jeong, H.; Cohen, D.E.; Cui, L.; Supinski, A.; Savas, J.N.; Mazzulli, J.R.; Yates, J.R.; Bordone, L.; Guarente, L.; Krainc, D. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat. Med. 2012 , 18 , 159–165. [ Google Scholar ] [ CrossRef ]
• Jiang, M.; Wang, J.; Fu, J.; Du, L.; Jeong, H.; West, T.; Xiang, L.; Peng, Q.; Hou, Z.; Cai, H.; et al. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat. Med. 2012 , 18 , 153–158. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Jiang, M.; Zheng, J.; Peng, Q.; Hou, Z.; Zhang, J.; Mori, S.; Ellis, J.L.; Vlasuk, G.P.; Fries, H.; Suri, V.; et al. Sirtuin 1 activator SRT2104 protects Huntington’s disease mice. Ann. Clin. Transl. Neurol. 2014 , 1 , 1047–1052. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Lee, M.; Ban, J.J.; Chung, J.Y.; Im, W.; Kim, M. Amelioration of huntington’s disease phenotypes by beta-lapachone is associated with increases in sirt1 expression, creb phosphorylation and pgc-1α deacetylation. PLoS ONE 2018 , 13 , e0195968. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Naia, L.; Rosenstock, T.R.; Oliveira, A.M.; Oliveira-Sousa, S.I.; Caldeira, G.L.; Carmo, C.; Laço, M.N.; Hayden, M.R.; Oliveira, C.R.; Rego, A.C. Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models. Mol. Neurobiol. 2017 , 54 , 5385–5399. [ Google Scholar ] [ CrossRef ]
• Smith, M.R.; Syed, A.; Lukacsovich, T.; Purcell, J.; Barbaro, B.A.; Worthge, S.A.; Wei, S.R.; Pollio, G.; Magnoni, L.; Scali, C.; et al. A potent and selective sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of huntington’s disease. Hum. Mol. Genet. 2014 , 23 , 2995–3007. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Hathorn, T.; Snyder-Keller, A.; Messer, A. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol. Dis. 2011 , 41 , 43–50. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Tulino, R.; Benjamin, A.C.; Jolinon, N.; Smith, D.L.; Chini, E.N.; Carnemolla, A.; Bates, G.P. SIRT1 activity is linked to its brain region-specific phosphorylation and is impaired in Huntington’s disease mice. PLoS ONE 2016 , 11 , e0145425. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Baldo, B.; Gabery, S.; Soylu-Kucharz, R.; Cheong, R.Y.; Henningsen, J.B.; Englund, E.; McLean, C.; Kirik, D.; Halliday, G.; Petersén, H.A. SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease. Neuropathol. Appl. Neurobiol. 2019 , 45 , 361–379. [ Google Scholar ] [ CrossRef ]
• Luthi-Carter, R.; Taylor, D.M.; Pallos, J.; Lambert, E.; Amore, A.; Parker, A.; Moffitt, H.; Smith, D.L.; Runne, H.; Gokce, O.; et al. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc. Natl. Acad. Sci. USA 2010 , 107 , 7927–7932. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Chopra, V.; Quinti, L.; Kim, J.; Vollor, L.; Narayanan, K.L.; Edgerly, C.; Cipicchio, P.M.; Lauver, M.A.; Choi, S.H.; Silverman, R.B.; et al. The Sirtuin 2 Inhibitor AK-7 Is Neuroprotective in Huntington’s Disease Mouse Models. Cell Rep. 2012 , 2 , 1492–1497. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Naia, L.; Carmo, C.; Campesan, S.; Fão, L.; Cotton, V.E.; Valero, J.; Lopes, C.; Rosenstock, T.R.; Giorgini, F.; Rego, A.C. Mitochondrial SIRT3 confers neuroprotection in Huntington’s disease by regulation of oxidative challenges and mitochondrial dynamics. Free Radic. Biol. Med. 2021 , 163 , 163–179. [ Google Scholar ] [ CrossRef ]
• Yeh, H.H.; Young, D.; Gelovani, J.G.; Robinson, A.; Davidson, Y.; Herholz, K.; Mann, D.M.A. Histone deacetylase class II and acetylated core histone immunohistochemistry in human brains with Huntington’s disease. Brain Res. 2013 , 1504 , 16–24. [ Google Scholar ] [ CrossRef ]
• Sharma, S.; Taliyan, R. Transcriptional dysregulation in Huntington’s disease: The role of histone deacetylases. Pharmacol. Res. 2015 , 100 , 157–169. [ Google Scholar ] [ CrossRef ]
• Bassi, S.; Tripathi, T.; Monziani, A.; Di Leva, F.; Biagioli, M. Epigenetics of huntington’s disease. In Advances in Experimental Medicine and Biology ; Springer New York LLC: New York, NY, USA, 2017; Volume 978, pp. 277–299. [ Google Scholar ]
• Sharma, S.; Sarathlal, K.C.; Taliyan, R. Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases. CNS Neurol. Disord. Drug Targets 2018 , 18 , 11–18. [ Google Scholar ] [ CrossRef ]
• Hockly, E.; Richon, V.M.; Woodman, B.; Smith, D.L.; Zhou, X.; Rosa, E.; Sathasivam, K.; Ghazi-Noori, S.; Mahal, A.; Lowden, P.A.S.; et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc. Natl. Acad. Sci. USA 2003 , 100 , 2041–2046. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Ferrante, R.J.; Kubilus, J.K.; Lee, J.; Ryu, H.; Beesen, A.; Zucker, B.; Smith, K.; Kowall, N.W.; Ratan, R.R.; Luthi-Carter, R.; et al. Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington’s Disease Mice. J. Neurosci. 2003 , 23 , 9418–9427. [ Google Scholar ] [ CrossRef ]
• Oliveira, J.M.A.; Chen, S.; Almeida, S.; Riley, R.; Gonçalves, J.; Oliveira, C.R.; Hayden, M.R.; Nicholls, D.G.; Ellerby, L.M.; Rego, A.C. Mitochondrial-dependent Ca2+ handling in Huntington’s disease striatal cells: Effect of histone deacetylase inhibitors. J. Neurosci. 2006 , 26 , 11174–11186. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Naia, L.; Cunha-Oliveira, T.; Rodrigues, J.; Rosenstock, T.R.; Oliveira, A.; Ribeiro, M.; Carmo, C.; Oliveira-Sousa, S.I.; Duarte, A.I.; Hayden, M.R.; et al. Histone deacetylase inhibitors protect against pyruvate dehydrogenase dysfunction in huntington’s disease. J. Neurosci. 2017 , 37 , 2776–2794. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Thomas, E.A.; Coppola, G.; Desplats, P.A.; Tang, B.; Soragni, E.; Burnett, R.; Gao, F.; Fitzgerald, K.M.; Borok, J.F.; Herman, D.; et al. The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington’s disease transgenic mice. Proc. Natl. Acad. Sci. USA 2008 , 105 , 15564–15569. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Jia, H.; Kast, R.J.; Steffan, J.S.; Thomas, E.A. Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington’s disease mice: Implications for the ubiquitin-proteasomal and autophagy systems. Hum. Mol. Genet. 2012 , 21 , 5280–5293. [ Google Scholar ] [ CrossRef ]
• Jia, H.; Wang, Y.; Morris, C.D.; Jacques, V.; Gottesfeld, J.M.; Rusche, J.R.; Thomas, E.A. The effects of pharmacological inhibition of histone deacetylase 3 (HDAC3) in Huntington’s disease mice. PLoS ONE 2016 , 11 , e0152498. [ Google Scholar ] [ CrossRef ]
• Chopra, V.; Quinti, L.; Khanna, P.; Paganetti, P.; Kuhn, R.; Young, A.B.; Kazantsev, A.G.; Hersch, S. LBH589, A Hydroxamic Acid-Derived HDAC Inhibitor, is Neuroprotective in Mouse Models of Huntington’s Disease. J. Huntingtons. Dis. 2016 , 5 , 347–355. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Bobrowska, A.; Paganetti, P.; Matthias, P.; Bates, G.P. Hdac6 knock-out increases tubulin acetylation but does not modify disease progression in the R6/2 mouse model of Huntington’s disease. PLoS ONE 2011 , 6 , e20696. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Üner, M.; Yener, G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspective. Int. J. Nanomed. 2007 , 2 , 289–300. [ Google Scholar ]
• Saraiva, C.; Praça, C.; Ferreira, R.; Santos, T.; Ferreira, L.; Bernardino, L. Nanoparticle-mediated brain drug delivery: Overcoming blood–brain barrier to treat neurodegenerative diseases. J. Control. Release 2016 , 235 , 34–47. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Chowdhury, A.; Kunjiappan, S.; Panneerselvam, T.; Somasundaram, B.; Bhattacharjee, C. Nanotechnology and nanocarrier-based approaches on treatment of degenerative diseases. Int. Nano Lett. 2017 , 7 , 91–122. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Poovaiah, N.; Davoudi, Z.; Peng, H.; Schlichtmann, B.; Mallapragada, S.; Narasimhan, B.; Wang, Q. Treatment of neurodegenerative disorders through the blood–brain barrier using nanocarriers. Nanoscale 2018 , 10 , 16962–16983. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Rakotoarisoa, M.; Angelova, A. Amphiphilic Nanocarrier Systems for Curcumin Delivery in Neurodegenerative Disorders. Medicines 2018 , 5 , 126. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Wilson, E.R.; Parker, L.M.; Orth, A.; Nunn, N.; Torelli, M.; Shenderova, O.; Gibson, B.C.; Reineck, P. The effect of particle size on nanodiamond fluorescence and colloidal properties in biological media. Nanotechnology 2019 , 30 , 385704. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ramachandran, S.; Thangarajan, S. A novel therapeutic application of solid lipid nanoparticles encapsulated thymoquinone (TQ-SLNs) on 3-nitroproponic acid induced Huntington’s disease-like symptoms in wistar rats. Chem. Biol. Interact. 2016 , 256 , 25–36. [ Google Scholar ] [ CrossRef ]
• Ramachandran, S.; Thangarajan, S. Thymoquinone loaded solid lipid nanoparticles counteracts 3-Nitropropionic acid induced motor impairments and neuroinflammation in rat model of Huntington’s disease. Metab. Brain Dis. 2018 , 33 , 1459–1470. [ Google Scholar ] [ CrossRef ]
• Bhatt, R.; Singh, D.; Prakash, A.; Mishra, N. Development, characterization and nasal delivery of rosmarinic acid-loaded solid lipid nanoparticles for the effective management of Huntingtons disease. Drug Deliv. 2015 , 22 , 931–939. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Niu, X.; Chen, J.; Gao, J. Nanocarriers as a powerful vehicle to overcome blood-brain barrier in treating neurodegenerative diseases: Focus on recent advances. Asian J. Pharm. Sci. 2019 , 14 , 480–496. [ Google Scholar ] [ CrossRef ]
• Bahmad, H.; Hadadeh, O.; Chamaa, F.; Cheaito, K.; Darwish, B.; Makkawi, A.-K.; Abou-Kheir, W. Modeling Human Neurological and Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Neuronal Differentiation and Its Applications in Neurotrauma. Front. Mol. Neurosci. 2017 , 10 , 1–17. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Connor, B. Concise Review: The Use of Stem Cells for Understanding and Treating Huntington’s Disease. Stem Cells 2018 , 36 , 146–160. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Holley, S.M.; Kamdjou, T.; Reidling, J.C.; Fury, B.; Coleal-Bergum, D.; Bauer, G.; Thompson, L.M.; Levine, M.S.; Cepeda, C. Therapeutic effects of stem cells in rodent models of Huntington’s disease: Review and electrophysiological findings. CNS Neurosci. Ther. 2018 , 24 , 329–342. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Kerkis, I.; Haddad, M.S.; Valverde, C.W.; Glosman, S. Neural and mesenchymal stem cells in animal models of Huntington’s disease: Past experiences and future challenges. Stem Cell Res. Ther. 2015 , 6 , 232. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Lo Furno, D.; Mannino, G.; Giuffrida, R. Functional role of mesenchymal stem cells in the treatment of chronic neurodegenerative diseases. J. Cell. Physiol. 2018 , 233 , 3982–3999. [ Google Scholar ] [ CrossRef ]
• Golas, M.M. Human cellular models of medium spiny neuron development and Huntington disease. Life Sci. 2018 , 209 , 179–196. [ Google Scholar ] [ CrossRef ]
• Colpo, G.D.; Furr Stimming, E.; Teixeira, A.L. Stem cells in animal models of Huntington disease: A systematic review. Mol. Cell. Neurosci. 2019 , 95 , 43–50. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Dunnett, S.B.; Carter, R.J.; Watts, C.; Torres, E.M.; Mahal, A.; Mangiarini, L.; Bates, G.; Morton, A.J. Striatal Transplantation in a Transgenic Mouse Model of Huntington’s Disease. Exp. Neurol. 1998 , 154 , 31–40. [ Google Scholar ] [ CrossRef ]
• van Dellen, A.; Deacon, R.; York, D.; Blakemore, C.; Hannan, A.J. Anterior cingulate cortical transplantation in transgenic Huntington’s disease mice. Brain Res. Bull. 2001 , 56 , 313–318. [ Google Scholar ] [ CrossRef ]
• Snyder, E.Y.; Yoon, C.; Flax, J.D.; Macklis, J.D. Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc. Natl. Acad. Sci. USA 1997 , 94 , 11663–11668. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Lee, J.P.; Jeyakumar, M.; Gonzalez, R.; Takahashi, H.; Lee, P.J.; Baek, R.C.; Clark, D.; Rose, H.; Fu, G.; Clarke, J.; et al. Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat. Med. 2007 , 13 , 439–447. [ Google Scholar ] [ CrossRef ]
• Yang, C.R.; Yu, R.K. Intracerebral transplantation of neural stem cells combined with trehalose ingestion alleviates pathology in a mouse model of Huntington’s disease. J. Neurosci. Res. 2009 , 87 , 26–33. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Fink, K.D.; Rossignol, J.; Crane, A.T.; Davis, K.K.; Bombard, M.C.; Bavar, A.M.; Clerc, S.; Lowrance, S.A.; Song, C.; Lescaudron, L.; et al. Transplantation of umbilical cord-derived mesenchymal stem cells into the striata of R6/2 mice: Behavioral and neuropathological analysis. Stem Cell Res. Ther. 2013 , 4 , 130. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Rossignol, J.; Fink, K.D.; Crane, A.T.; Davis, K.K.; Bombard, M.C.; Clerc, S.; Bavar, A.M.; Lowrance, S.A.; Song, C.; Witte, S.; et al. Reductions in behavioral deficits and neuropathology in the R6/2 mouse model of Huntington’s disease following transplantation of bone-marrow-derived mesenchymal stem cells is dependent on passage number. Stem Cell Res. Ther. 2015 , 6 , 9. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Giampà, C.; Alvino, A.; Magatti, M.; Silini, A.R.; Cardinale, A.; Paldino, E.; Fusco, F.R.; Parolini, O. Conditioned medium from amniotic cells protects striatal degeneration and ameliorates motor deficits in the R6/2 mouse model of Huntington’s disease. J. Cell. Mol. Med. 2019 , 23 , 1581–1592. [ Google Scholar ] [ CrossRef ]
• Reidling, J.C.; Relaño-Ginés, A.; Holley, S.M.; Ochaba, J.; Moore, C.; Fury, B.; Lau, A.; Tran, A.H.; Yeung, S.; Salamati, D.; et al. Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington’s Disease Mice. Stem Cell Reports 2018 , 10 , 58–72. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Dey, N.D.; Bombard, M.C.; Roland, B.P.; Davidson, S.; Lu, M.; Rossignol, J.; Sandstrom, M.I.; Skeel, R.L.; Lescaudron, L.; Dunbar, G.L. Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behav. Brain Res. 2010 , 214 , 193–200. [ Google Scholar ] [ CrossRef ]
• Al-Gharaibeh, A.; Culver, R.; Stewart, A.N.; Srinageshwar, B.; Spelde, K.; Frollo, L.; Kolli, N.; Story, D.; Paladugu, L.; Anwar, S.; et al. Induced pluripotent stem cell-derived neural stem cell transplantations reduced behavioral deficits and ameliorated neuropathological changes in YAC128 mouse model of Huntington’s disease. Front. Neurosci. 2017 , 11 , 628. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Wang, Y.L.; Liu, W.; Wada, E.; Murata, M.; Wada, K.; Kanazawa, I. Clinico-pathological rescue of a model mouse of Huntington’s disease by siRNA. Neurosci. Res. 2005 , 53 , 241–249. [ Google Scholar ] [ CrossRef ]
• DiFiglia, M.; Sena-Esteves, M.; Chase, K.; Sapp, E.; Pfister, E.; Sass, M.; Yoder, J.; Reeves, P.; Pandey, R.K.; Rajeev, K.G.; et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc. Natl. Acad. Sci. USA 2007 , 104 , 17204–17209. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Bilsen, P.H.J.V.; Jaspers, L.; Lombardi, M.S.; Odekerken, J.C.E.; Burright, E.N.; Kaemmerer, W.F. Identification and allele-specific silencing of the mutant huntingtin allele in Huntington’s disease patient-derived fibroblasts. Hum. Gene Ther. 2008 , 19 , 710–718. [ Google Scholar ] [ CrossRef ]
• Lombardi, M.S.; Jaspers, L.; Spronkmans, C.; Gellera, C.; Taroni, F.; Di Maria, E.; Di Donato, S.; Kaemmerer, W.F. A majority of Huntington’s disease patients may be treatable by individualized allele-specific RNA interference. Exp. Neurol. 2009 , 217 , 312–319. [ Google Scholar ] [ CrossRef ]
• Jimenez-Sanchez, M.; Lam, W.; Hannus, M.; Sönnichsen, B.; Imarisio, S.; Fleming, A.; Tarditi, A.; Menzies, F.; Ed Dami, T.; Xu, C.; et al. SiRNA screen identifies QPCT as a druggable target for Huntington’s disease. Nat. Chem. Biol. 2015 , 11 , 347–354. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Ban, J.J.; Chung, J.Y.; Lee, M.; Im, W.; Kim, M. MicroRNA-27a reduces mutant hutingtin aggregation in an in vitro model of Huntington’s disease. Biochem. Biophys. Res. Commun. 2017 , 488 , 316–321. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Drouet, V.; Ruiz, M.; Zala, D.; Feyeux, M.; Auregan, G.; Cambon, K.; Troquier, L.; Carpentier, J.; Aubert, S.; Merienne, N.; et al. Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells. PLoS ONE 2014 , 9 , e99341. [ Google Scholar ] [ CrossRef ]
• Boudreau, R.L.; McBride, J.L.; Martins, I.; Shen, S.; Xing, Y.; Carter, B.J.; Davidson, B.L. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Mol. Ther. 2009 , 17 , 1053–1063. [ Google Scholar ] [ CrossRef ]
• McBride, J.L.; Pitzer, M.R.; Boudreau, R.L.; Dufour, B.; Hobbs, T.; Ojeda, S.R.; Davidson, B.L. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol. Ther. 2011 , 19 , 2152–2162. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Huang, B.; Schiefer, J.; Sass, C.; Landwehrmeyer, G.B.; Kosinski, C.M.; Kochanek, S. High-capacity adenoviral vector-mediated reduction of huntingtin aggregate load in vitro and in vivo. Hum. Gene Ther. 2007 , 18 , 303–311. [ Google Scholar ] [ CrossRef ]
• Grimm, D.; Streetz, K.L.; Jopling, C.L.; Storm, T.A.; Pandey, K.; Davis, C.R.; Marion, P.; Salazar, F.; Kay, M.A. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 2006 , 441 , 537–541. [ Google Scholar ] [ CrossRef ]
• McBride, J.L.; Boudreau, R.L.; Harper, S.Q.; Staber, P.D.; Monteys, A.M.; Martins, I.; Gilmore, B.L.; Burstein, H.; Peluso, R.W.; Polisky, B. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: Implications for the therapeutic development of RNAi. Proc. Natl. Acad. Sci. USA 2008 , 105 , 5868–5873. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Aguiar, S.; van der Gaag, B.; Cortese, F.A.B. RNAi mechanisms in Huntington’s disease therapy: siRNA versus shRNA. Transl. Neurodegener. 2017 , 6 , 30. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Keeler, A.M.; Sapp, E.; Chase, K.; Sottosanti, E.; Danielson, E.; Pfister, E.; Stoica, L.; Difiglia, M.; Aronin, N.; Sena-Esteves, M. Cellular Analysis of Silencing the Huntington’s Disease Gene Using AAV9 Mediated Delivery of Artificial Micro RNA into the Striatum of Q140/Q140 Mice. J. Huntingt. Dis. 2016 , 5 , 239–248. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Pfister, E.L.; Chase, K.O.; Sun, H.; Kennington, L.A.; Conroy, F.; Johnson, E.; Miller, R.; Borel, F.; Aronin, N.; Mueller, C. Safe and efficient silencing with a Pol II, but not a Pol lII, promoter expressing an artificial miRNA targeting human huntingtin. Mol. Ther. Nucleic Acids 2017 , 7 , 324–334. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Jinek, M.; Chylinski, K.; Fonfara, I.; Hauer, M.; Doudna, J.A.; Charpentier, E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 2012 , 337 , 816–821. [ Google Scholar ] [ CrossRef ]
• Shin, J.W.; Kim, K.H.; Chao, M.J.; Atwal, R.S.; Gillis, T.; MacDonald, M.E.; Gusella, J.F.; Lee, J.M. Permanent inactivation of Huntington’s disease mutation by personalized allele-specific CRISPR/Cas9. Hum. Mol. Genet. 2016 , 25 , 4566–4576. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Dabrowska, M.; Juzwa, W.; Krzyzosiak, W.J.; Olejniczak, M. Precise excision of the CAG tract from the huntingtin gene by Cas9 nickases. Front. Neurosci. 2018 , 12 , 75. [ Google Scholar ] [ CrossRef ]
• Yang, S.; Chang, R.; Yang, H.; Zhao, T.; Hong, Y.; Kong, H.E.; Sun, X.; Qin, Z.; Jin, P.; Li, S.; et al. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. J. Clin. Investig. 2017 , 127 , 2719–2724. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Merienne, N.; Vachey, G.; de Longprez, L.; Meunier, C.; Zimmer, V.; Perriard, G.; Canales, M.; Mathias, A.; Herrgott, L.; Beltraminelli, T.; et al. The Self-Inactivating KamiCas9 System for the Editing of CNS Disease Genes. Cell Rep. 2017 , 20 , 2980–2991. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Kosicki, M.; Tomberg, K.; Bradley, A. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Nat. Biotechnol. 2018 , 36 , 765–771. [ Google Scholar ] [ CrossRef ]
• Tabrizi, S.J.; Ghosh, R.; Leavitt, B.R. Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease. Neuron 2019 , 102 , 801–819. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Sledzinski, P.; Dabrowska, M.; Nowaczyk, M.; Olejniczak, M. Paving the way towards precise and safe CRISPR genome editing. Biotechnol. Adv. 2021 , 49 , 107737. [ Google Scholar ] [ CrossRef ]
• Li, J.Y.; Popovic, N.; Brundin, P. The use of the R6 transgenic mouse models of Huntington’ s disease in attempts to develop novel therapeutic strategies. NeuroRx 2005 , 2 , 447–464. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Olanow, C.W.; Wunderle, K.B.; Kieburtz, K. Milestones in movement disorders clinical trials: Advances and landmark studies. Mov. Disord. 2011 , 26 , 1003–1014. [ Google Scholar ] [ CrossRef ]
• Ravina, B.; Romer, M.; Constantinescu, R.; Biglan, K.; Brocht, A.; Kieburtz, K.; Shoulson, I.; McDermott, M.P. The relationship between CAG repeat length and clinical progression in Huntington’s disease. Mov. Disord. 2008 , 23 , 1223–1227. [ Google Scholar ] [ CrossRef ]
• Stout, J.C.; Jones, R.; Labuschagne, I.; O’Regan, A.M.; Say, M.J.; Dumas, E.M.; Queller, S.; Justo, D.; Dar Santos, R.; Coleman, A.; et al. Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 2012 , 83 , 687–694. [ Google Scholar ] [ CrossRef ]

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Kim, A.; Lalonde, K.; Truesdell, A.; Gomes Welter, P.; Brocardo, P.S.; Rosenstock, T.R.; Gil-Mohapel, J. New Avenues for the Treatment of Huntington’s Disease. Int. J. Mol. Sci. 2021 , 22 , 8363. https://doi.org/10.3390/ijms22168363

Kim A, Lalonde K, Truesdell A, Gomes Welter P, Brocardo PS, Rosenstock TR, Gil-Mohapel J. New Avenues for the Treatment of Huntington’s Disease. International Journal of Molecular Sciences . 2021; 22(16):8363. https://doi.org/10.3390/ijms22168363

Kim, Amy, Kathryn Lalonde, Aaron Truesdell, Priscilla Gomes Welter, Patricia S. Brocardo, Tatiana R. Rosenstock, and Joana Gil-Mohapel. 2021. "New Avenues for the Treatment of Huntington’s Disease" International Journal of Molecular Sciences 22, no. 16: 8363. https://doi.org/10.3390/ijms22168363

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Review of Huntington’s Disease: From Basics to Advances in Diagnosis and Treatment

We conducted the present review facing the enormous growth of scientific knowledge in Huntington’s disease (HD) and the need for a practical update for general neurologists. HD is a devastating neurodegenerative disease of autosomal dominant inheritance and full penetrance, caused by an expansion of the cytosine-adenine-guanine (CAG) trinucleotide in the huntingtin gene located on chromosome 4. The clinical phenotype varies according to the age of presentation, but it is mainly characterized by cognitive, motor and psychiatric disturbances. Many mechanisms were raised trying to explain the path to neurodegeneration, including disruption of proteostasis, transcription and mitochondrial dysfunction as well as direct toxicity. There has been tremendous progress regarding disease pathogenesis, clinical management and promising new therapeutic avenues including disease-modifying treatments that pose a challenge and a need for a practical approach to be taken by movement disorders specialists and general neurologists.

) ) recommendations for manuscripts submitted to biomedical journals, the Committee on Publication Ethics ( ) guidelines, and the of Transparency and Best Practice in Scholarly Publishing. website: www.neurores.org   editorial contact: [email protected]    [email protected] Address: 9225 Leslie Street, Suite 201, Richmond Hill, Ontario, L4B 3H6, Canada © Elmer Press Inc. All Rights Reserved. : The views and opinions expressed in the published articles are those of the authors and do not necessarily reflect the views or opinions of the editors and Elmer Press Inc. This website is provided for medical research and informational purposes only and does not constitute any medical advice or professional services. The information provided in this journal should not be used for diagnosis and treatment, those seeking medical advice should always consult with a licensed physician. Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. View all journals Explore content About the journal Publish with us Sign up for alerts Open access Published: 08 July 2024 Sex contribution to average age at onset of Huntington’s disease depends on the number of (CAG) n repeats Anna Stanisławska-Sachadyn 1 , 2 , 3 , Michał Krzemiński 4 , Daniel Zielonka 5 , Magdalena Krygier 6 , Ewa Ziętkiewicz 7 , Jarosław Sławek 8 , 9 , Janusz Limon 10 & REGISTRY investigators of the European Huntington’s Disease Network (EHDN) Scientific Reports volume  14 , Article number:  15729 ( 2024 ) Cite this article 2058 Accesses Metrics details Huntington's disease Medical genetics Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the extension of the CAG repeats in exon 1 of the HTT gene and is transmitted in a dominant manner. The present study aimed to assess whether patients’ sex, in the context of mutated and normal allele length, contributes to age on onset (AO) of HD. The study population comprised a large cohort of 3723 HD patients from the European Huntington’s Disease Network’s REGISTRY database collected at 160 sites across 17 European countries and in one location outside Europe. The data were analyzed using regression models and factorial analysis of variance (ANOVA) considering both mutated allele length and sex as predictors of patients’ AO. AO, as described by the rater’s estimate, was found to be later in affected women than in men across the whole population. This difference was most pronounced in a subgroup of 1273 patients with relatively short variants of the mutated allele (40–45 CAG repeats) and normal alleles in a higher half of length distribution—namely, more than 17 CAG repeats; however, it was also observed in each group. Our results presented in this observational study point to sex-related differences in AO, most pronounced in the presence of the short mutated and long normal allele, which may add to understanding the dynamics of AO in Huntington’s Disease. Trial registration : ClinicalTrials.gov identifier NCT01590589. Similar content being viewed by others Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1 Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range Attenuated huntingtin gene CAG nucleotide repeat size in individuals with Lynch syndrome Introduction. Huntington’s disease (HD) is an autosomal dominant, progressive, neurodegenerative disorder characterized by motor symptoms, cognitive impairment, and psychiatric disturbances. The prevalence of HD is 6.37 and 8.87 per 100,000 people in Europe and North America, respectively, while it is much less prevalent in Africa and Asia 1 . It is caused by an expansion of the trinucleotide CAG tandem repeat (> 35 CAGs) located in exon 1 of the HTT gene encoding the huntingtin protein. Huntingtin’s cellular functions are not fully understood, although mutant huntingtin is known to be digested into fragments, which build toxic aggregates that disrupt transcription processes and cytoplasmic transport 2 . This leads to mitochondrial dysfunction, altered reactive oxygen species defense, and finally, apoptosis resulting in neuronal dysfunction. The onset of the disease usually occurs in midlife. Age at onset (AO) is strongly associated with the length of the (CAG) n expansion in the mutated allele, such that the longer the expanded repeat is, the earlier the onset of clinical symptoms will manifest. Mutated alleles that carry at least 40 repeats are fully penetrant 3 . Expanded alleles ranging from 40 to 45 repeats are observed most often. A considerable variance in AO has been observed in individuals who carry the (CAG) n expansion at comparable lengths, prompting the search for modifying factors that may account for the varying AO. The length of CAG repeats is responsible for approximately 50–70% of the variability of AO in HD 2 . The mutated HTT is highly unstable, and both extensions and contractions of the mutated allele in inter-generational transmissions are observed in HD 4 . Interestingly, the sex of a mouse embryo has an impact on the likelihood of CAG repeat contractions or expansions, which has led to suggestions that the change in CAG repeat number may also be a post-zygotic event 5 , 6 . In humans, it has been observed that the mutated allele may contract when inherited from mother 7 , 8 . Notably, 42% of maternally transmitted alleles contracted when passed to daughters and only 27% when passed to sons 9 . The above observation led to a suggestion that both parental and offspring sex plays a role in HD pathology. Interestingly, data regarding the impact of sex on AO of HD are relatively scarce 10 , 11 , 12 , 13 , and it is clear that the involvement of the patient’s sex in the AO of HD should be further evaluated in the context of the size of the mutated allele. In recent years it has been noticed that the expansion of CAG triplets occurs not only in germinal but also in somatic cells, including the nervous system—specifically, in human striatal cells—and is an early event in the disease course 14 . CAG trinucleotide instability has been observed in non-dividing cells 15 , 16 , it has been demonstrated that the expansions of a mutated allele in the cortex 17 and in the post-mitotic striatum 16 determine the AO of HD. The mechanism by which expansions arise may be a consequence of the physiological processes present in somatic cells 17 . It has been recently established that more genetic factors are involved in the mechanism by which the expansion in non-dividing cells arises. Somatic instability is dependent on the presence of mismatch repair proteins—namely Msh2 18 , Msh3 and Mlh1 19 , Msh2-Msh3 form MutS-beta heterodimer recognizing and binding CAG loops. In the genome-wide association study (GWAS), other DNA repair system genes—the FAN1 and the RRM2B —have been identified as genetic factors that underlie variation in AO 20 . The FAN1 gene encodes a nuclease involved in inter-strand DNA crosslink repair that is necessary for controlling CAG repeat expansion 21 . Another GWAS study confirmed that the MLH1 gene is a factor modifying AO in HD 22 . It has been further hypothesized that the mismatch repair system (MMR) may introduce expansion while correcting for misalign of DNA strands during its reannealing, either in the course of DNA replication in dividing cells or RNA transcription in non-dividing cells, in a process initialized by binding of PCNA and MutS-beta 23 . Apart from the mutated allele, the role of a normal allele in HD pathogenesis has been also considered. The negative correlation between AO and the normal CAG repeat number has been reported to be sex-specific and stronger for normal maternal allele transmissions 24 . Irrespective of the patient’s sex a negative correlation between AO and the normal paternal allele size has also been reported 25 . Interestingly, results of analyses of 337 inter-generational transmissions indicate that, in patients who inherit the expanded allele from their mothers, the increased frequency of mutated allele contractions has been associated with longer normal alleles 26 , pointing at differences in the interplay between mutated and normal alleles between sexes in trans-generational length changes. Next, larger normal alleles in combination with shorter mutated alleles were associated with earlier AO and vice versa — in combination with longer mutated alleles—with later AO, in a group of 921 subjects 27 . Similarly, the longest normal alleles were linked to later AO when combined with long expanded alleles 28 . Nevertheless, no impact of the normal allele length on motor onset along the mutated allele length was found in multiple linear regression analyses in a large population of 4067 subjects 29 . The present understanding of the impact of a variety of factors on AO of HD remains not fully solved. The present study aimed to test the extent to which the sex of affected individuals can impact AO of HD in the context of the length of CAG repeats within large and normal alleles. The analyses were conducted in a large-scale, multi-national cohort of European ancestry. This observational study supported by statistical analyses adds to understanding the pathogenesis of HD in a way that could not be achieved in animal or cellular models. Study population Analyses were performed on data extracted from the REGISTRY database provided by the European Huntington’s Disease Network (EHDN). The data were obtained as part of the EDHN’s data mining project 0636. REGISTRY data were collected at 160 sites across in 18 countries (17 European and one country outside Europe) from June 2004 and were assessed in November 2017. Given that the data required to perform the analyses were not available for all the HD patients included in the REGISTRY database, the selection of the study population was necessary. The criteria for including subjects were (i) the number of (CAG) n repeats in the expanded allele equal to or higher than 36 (10,363 subjects) and (ii) the availability of the clinician’s best estimate of AO—referred to as the rater’s estimate that reflects most probable onset age based on experienced professional interview with patient and family members or onset established examining person observed from premanifest HD stage, the number of (CAG) n repeats in the normal allele, if available, lower than 36 (3723 subjects). The rater’s estimate of AO was calculated based on the “sxrater,” which is coded as a date in the REGISTRY database. The EHDN investigators’ AO estimation was used in analyzes. The data on the (CAG) n allele length were from the EHDN database or, if not available, from the local laboratory. The number of repeated CAG units in the expanded allele ranged from 36 to 90. AO was analyzed in the context of patients’ sex in a group of 3723 patients (see Table 1 for further details). Ethical approval for REGISTRY was obtained in each participating country. All participants gave written informed consent: https://www.enroll-hd.org/enrollhd_documents/2016-10-R1/registry-protocol-3.0.pdf . The REGISTRY protocol was approved by the EHDN Scientific and Bioethics Advisory Committee. Statistical analyses Multiple regression models to estimate the variance in patients’ AO were created. The regression coefficients from the analyzed models were used to assess the proportion of variance in patients’ AO (the outcome measure) explained by mutated allele length and the other predictor variable: the sex of HD patients or a type of first symptoms. Regression coefficients were calculated while the expanded allele sizes were median-centered for 43 CAG repeats. The interaction terms between the mutated allele length and patients’ sex were not significant in any of the models (Table 2 , models A–F); therefore, models without interaction terms were chosen. In multiple linear regression models designed to determine whether the impact of a first symptom type differed between sexes, the significance of the interaction coefficients term between the patient’s sex and type of first symptoms were of interest. In simple linear regression analyses, the coefficient of determination (R 2 ) was used to assess the proportion of variance in AO explained by the predictor variable. A two-way ANOVA using a generalized linear model with the LSMEAN statement and Tukey post-hoc test was performed. The association between AO and the number of (CAG) n repeats in the mutated allele with the impact of patients’ sex was assessed using factorial analyses with a two between-subjects factor. In both the factorial and regression analyses, AO, which was a dependent variable, was natural log-transformed 30 . The normality of the distributions was assessed using the Kolmogorov–Smirnov test. In the ranked analyses, the significance of differences between the groups was determined using the Wilcoxon rank–sum test, corrected for multiple comparisons using the Bonferroni method when necessary. Chi-square statistics were used to test the difference in distribution of the categorical variables (e.g., frequency of first symptom types between sexes). Correlations between the number of CAG repeats within either normal or mutated allele, and the AO values were calculated using Spearman statistics. The level of significance was set at 0.05. The statistical analyses were carried out using SAS versions 9.3 and 9.4 (NC, USA) and the R platform. Population stratifications Several analyses were performed in subgroups defined according to the ranges of the expanded allele size: ≤ 39 (CAG) n , 40–45 (CAG) n , 46–50 (CAG) n , and > 50 (CAG) n . Subjects in group 1 had alleles of 39 CAG repeats or fewer, which are not fully penetrant 3 . Carriers of penetrant and mid-size mutation of 40–50 CAGs had an average age at onset HD. They are the majority of HD patients whose disease is characterized by a large diversity in AO; thus, it was further divided into group 2, including subjects who had expanded alleles of 40–45 CAGs, and group 3 who had expanded alleles of 46–49 CAGs. Subjects in group 4 carried mutation longer than 50 CAGs and had juvenile form of HD. Expanded alleles described 27.85% of the variance in AO among 2617 carriers of 40–45 CAGs (70.25% of those for whom sex, AO, and mutated allele length were available), 10.68% among 757 carriers of 46–50 CAGs, and 60.04% among 255 carriers of alleles longer than 50 CAGs, who established an early-onset subgroup. Thus, the coefficient of determination (R2) in regression models, which is used to assess the proportion of variance in AO explained by the expanded allele size in the whole cohort is highly influenced by the characteristics of early-onset subjects, for whom genetic factor plays the strongest role in HD pathogenesis. Thus, the precision in determining the influence of an additional factor on AO, specifically of the patient’s sex, increases in analyses conducted among subgroups of mutated allele sizes, which certainly have a dominant impact. Moreover, in several analyses, the population has been stratified into two groups regarding the size of a normal allele, that is, below/equal to and above a median value of 17 CAGs. Subjects in a group of lower normal allele length distribution carried 8–17 CAG repeats, while subjects in a group of higher normal allele length distribution carried 18–35 CAG repeats. Data distribution and basic statistics A clinician’s best estimate of AO (i.e., rater’s estimated AO) and expanded allele length were available for 3723 subjects: men accounted for 47.95% and women for 52.05% (Table 1 ). Data pertaining to normal alleles were available for 3643 subjects. The frequencies of the first symptom types, as listed in rater’s estimate, were comparable between women and men (P = 0.2294, Table 1 ), although a slightly higher proportion of men first observed motor (52.82%) and cognitive symptoms (7.90%) compared to women (51.48% and 6.71%, respectively), while more women first observed mixed symptoms (19.76%) than men did (17.95%). These differences between sexes were non-significant, whether assessed using chi-square statistics (Table 1 ) or multiple regression analyses, which showed that the interaction term between the patient’s sex and the first symptom types did not contribute significantly to explaining the proportion of variance in AO (data not presented). A simple group comparison revealed no statistically significant difference in AO between men and women (Table 1 ). The median AO was 44 years for men and 45 for women ( P  = 0.0793), while the median length of the expanded allele was 43 for both men and women ( P  = 0.4376). As expected, the mutation size correlated highly with AO both in women and men (r = − 0.75863, r = − 0.76530, respectively; both P  < 0.0001). In the study population analyzed as a whole, the size of a mutated allele described 60.65% of the variance in AO—61.30% in women and 60.18% in men. Association between patients’ sex and age at onset in the context of mutated allele length In the whole study population, in regression models describing the proportion of variance in AO and involving the mutated allele length and patient sex as two predictor variables, sex was significantly involved in the AO variability ( P  = 0.0012; Table 2 A). After the cohort was divided with respect to mutation size, this association stayed significant among those subjects who had 40–45 CAG repeats ( P  = 0.0006; Table 3 B) but not in those who had ≤ 39 (CAG) n , 46–50 (CAG) n and > 50 (CAG) n (data not presented). Similarly, in two-way ANOVA LSMEAN analyzes, patients’ sex had a significant impact on AO variability across the entire study population ( P  = 0.0004; Table 3 A, Fig.  1 A). In those analyzes, unlike in the regression models, the mean AO is assessed by ANOVA between women and men for each mutated allele of the same size. Since no interaction between the length of a mutated allele and patients’ sex was found, analysis of type II was chosen 31 . In analyses performed in subgroups defined by the range of mutated allele length, patient sex had a significant impact on AO variance ( P  = 0.0005; Table 3 B) among those subjects who had 40–45 CAG repeats. The subgroup of HD patients who had expanded allele of 40–45 CAG repeats was characterized by high variance in AO, ranging from the age of 5 to 83; the median AO was 48 years (mean ± SD; 48.68 ± 9.99). Analyzes in ranges to evaluate differences in AO between women and men in the context of mutated allele length are presented in Supplementary Table S1 . Association between patients’ sex and age at onset in the context of the length of both mutated and normal alleles To evaluate whether the association between AO and patient sex might be impacted by the number of repeats within a normal allele, the study population has been stratified by the normal allele length ranges into the lower or higher half of distribution. In the multiple regression models, patient sex was a significant factor among those who had a normal allele in the higher half of length distribution, that is, 18–35 CAG repeats ( P  = 0.0007; Table 2 C) but not among those who had normal allele equal to or shorter than 17 CAG repeats ( P  = 0.2615; Table 2 D). When the population was stratified according to both mutated and normal allele length ranges, the results remained significant among those who had a mutated allele of 40–45 CAGs and a normal allele in the higher half of the length distribution ( P  < 0.0001; Table 2 E). Interestingly, in this group, sex accounted for 0.80% of variation in AO ( P  = 0.0014), as assessed by simple regression analyses (data not presented). Given the complex nature of AO distribution in HD, this association appears to be quite meaningful for a binary factor such as patients’ sex. Analogously, in factorial two-way ANOVA LSMEAN analyses, the difference in AO between affected women and men was significant only among those subjects whose normal allele length was in the higher half of the length distribution (Table 2 C, Fig.  1 B). This association was particularly pronounced in patients who also had 40–45 CAG repeats in the mutated allele and normal allele in a higher half of allele distribution ( P  < 0.0001; Table 3 E, Fig.  1 B, intercept). Overall, the mean AO in women and men in the subgroup of 40–45 CAG repeats in the mutated allele and 18–35 CAG repeats in the normal allele was 49.40 ± 9.64 and 47.70 ± 10.03 years, respectively ( P  = 0.0071). The difference in mean AO between females and males varied from 0.55 years for those with the mutated allele of 40 CAG repeats—to 2.23 years for those with the mutated allele of 44 CAG repeats. Analyses in ranges to evaluate differences in AO between women and men in the context of both mutated and normal allele length are presented in Supplementary Table S2 . Age at onset of male and female patients in relation to the number of CAG repeats within the mutated allele ( A ) across the entire study group ( B ) among subjects who carry more than 17 CAG repeats within the normal allele (higher half of the length distribution), inset: analyses for subjects with mutated allele (CAG) n  = 40–45. Two-way ANOVA and regression analyses were performed with natural log-transformed AO. Expansion of CAG repeats is a well-documented HD-determining factor that was first identified during the 1990s. AO is negatively correlated with increasing number of repeats in the mutated allele, with the longest alleles (> 50 CAG repeats) determining a juvenile-onset disease. However, in patients with shorter mutated alleles a high variability in AO is observed. This has prompted a search for factors that may contribute to the variance in AO of HD. We observed the impact of patients’ sex on AO of HD, in analyses that exclusively included subjects for whom the rater’s estimation of AO was known. Analysis of the entire study population revealed that patients’ sex was a significant factor in the variation in AO. However, among those who carried 40–45 CAG repeats, females’ AO was distinctly later than that of males. This finding comes as a surprise because earlier such observation has never been confirmed. The first estimation of sex involvement was made before the measurement of mutated allele size became a clinical practice 13 . No difference in AO between women and men among 2068 subjects 10 , among 151 subjects 32 or in residual AO of diagnostic motor signs, in the study including 4793 subjects 11 , has been identified through group comparison analyses. Moreover, no difference in age of clinical HD diagnosis between sexes, among 2145 HD patients, was found when the analysis was controlled for the specially invented score, calculation of which involved the individual’s current age and repeat length 12 . It should be acknowledged that the group examined in the present study was of a relatively large size of 3723 subjects. A further advantage of our work was the use of the clinician’s (the rater’s) best estimate of AO and the type of statistical analyses that we applied. Although residual AO calculation involves CAG repeat length 11 , two-way ANOVA compares the AO of women and men for each mutated allele while multiple regression analyzes include mutated allele as a linear variable. Our initial observation made in the analyzes of the whole study population was followed by the selection of a group among whom the difference in AO reaches higher significance. Given that the poly-Q mutation in the HTT is highly dynamic in brain tissue, leading to its mosaicism 14 , 16 , 17 , 33 , 34 , 35 , our results may suggest that either the enlargement of expansion size or the prevalence of enlargements may be higher in terminally differentiated male neurons; alternatively, the increase in contraction size or its prevalence might be higher in terminally differentiated female neurons. If so, such somatic sex-related differences in repeat instabilities may underlie our observation. Since the inter-generational and somatic changes might follow a similar direction, the data regarding inter-generational changes in expansion length may add to explaining the possible mechanism behind our observation. When parents’ and offspring’s sexes were considered in inter-generational analyses, mother–to–daughter contractions were reported 7 , 9 . Moreover, in mice sired by the same fathers, sex-related differences in expansion stability have been reported since expansions of the mutated allele were more frequent in males, while contractions were more frequent in females 5 . Also, several genetic variants have been found to affect AO of HD in a sex-related manner. Recently, variants within the MSH3 / DHFR locus—a proven source of the dynamic mutation instability in finally differentiated brain tissue 19 —have been found to be stronger modifiers of the diagnostic motor signs in women when analyses were set as sex-specific 11 . Moreover, X-chromosome-wide association study (XWAS) found a variant close to the moesin gene potentially modifying AO 36 . Differences in AO of HD between genders have previously been reported for carriers of different genotypes within the APOE gene 24 . We may speculate that those or other variants might be associated with sex-specific differences in neuronal mosaicism and thus disease AO. A neuroprotective effect of 17ß-estradiol has been reported in rats carrying mutations of 51 CAG repeats 37 . It has been demonstrated that in neuroblastoma cells estrogen enhances the expression of huntingtin and neuroglobin, which are then complexed and bind to mitochondria in response to H 2 O 2 stress to prevent apoptosis; these processes are abandoned in the case of mutated huntingtin 38 . Moreover, higher mtDNA levels have been observed in leukocytes from women with HD compared to men with HD 39 , which may be associated with a protective effect against oxidative stress in females. Our findings suggest that different factors may be associated with AO between subjects who carry 40–45 CAG repeats and have average AO and those who carry longer mutated alleles and thus have earlier AO. It is well-established that juvenile HD and average-onset HD differ at the molecular level: neurons with intranuclear inclusions composed of huntingtin are observed more frequently in juvenile patients, while extracellular structures with the morphology of dystrophic neuritis dominate in the central nervous system of adult-onset patients 40 . Further, for subjects who carried a normal allele in the higher half of its length distribution (i.e., more than 17 CAG repeats), the difference in AO between sexes was even more pronounced. The impact of the normal allele length on HD pathogenesis has been considered previously 24 , 25 , 27 , 28 , 41 . Interestingly, inter-generational contractions were more frequent when mothers carried long normal alleles 26 . Normal allele length has been demonstrated to impact AO in a manner dependent on the number of repeats in the mutated allele 27 , with long normal alleles reducing AO in the presence of the short mutated alleles. These data lead us to repeat the speculation that expansion occurs more frequently in male somatic cells of brain tissue while contractions occur more frequently in female cells—specifically, in the presence of the short mutated and long normal allele, leading to us observing the difference in AO between women and men in the presence of this constitutive blood genotype. This hypothesis, however, requires further investigation. We conducted our analyses in a large study group comprising 3723 subjects from the EHDN REGISTRY database, which is a multi-center, multi-national, prospective, observational study of HD. The diversity of study population combined with the standardized data from patients’ examinations is the present study’s strength. However, the estimation of AO constitutes a weakness of our study. The rater’s confidence level was high for 69.91% of AO estimations in our study group. However, AO was estimated retrospectively, the estimations might have been based on family reports, sometimes several years after the onset, which could lead to a bias in AO. Moreover, the data on the CAG number within both the expanded and normal alleles have been determined in several centres, including the EHDN and local laboratories, which might contribute to a bias in our results. In conclusion, we have presented analyses indicating that AO depends on the patient’s gender with regard to the sizes of both the mutated and the normal alleles. For patients who carry 40–45 CAG repeats, AO occurred later in females than in males. This association was stronger when the normal allele was in the upper range of the size distribution (that is, it was longer than 17 CAG repeats). Finally, the most pronounced difference in AO between sexes was observed among 1273 patients combining the above mentioned stratifications—in those with the mutation of 40–45 CAG repeats and normal allele longer than 17 CAG repeats. Data availability The REGISTRY data are not publicly available and are granted by the EHDN to qualified researchers given institutional assurance regarding patients’ data confidentiality. Anonymized patient data are granted from the EHDN following the standard submission procedure ( https://ehdn.org/hd-clinicians-researchers/data-mining-projects-2/ ). Further information and data requests should be directed to Anna Stanisławska-Sachadyn ([email protected]). Medina, A., Mahjoub, Y., Shaver, L. & Pringsheim, T. Prevalence and incidence of Huntington’s disease: An updated systematic review and meta-analysis. Mov. Disord. 37 , 2327–2335. https://doi.org/10.1002/mds.29228 (2022). Article   PubMed   PubMed Central   Google Scholar   Ross, C. A. & Tabrizi, S. J. Huntington’s disease: From molecular pathogenesis to clinical treatment. Lancet. Neurol. 10 , 83–98. https://doi.org/10.1016/s1474-4422(10)70245-3 (2011). Article   CAS   PubMed   Google Scholar   Ross, C. A. et al. Huntington disease: Natural history, biomarkers and prospects for therapeutics. Nat. Rev. Neurol. 10 , 204–216. https://doi.org/10.1038/nrneurol.2014.24 (2014). Duyao, M. et al. Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat. Genet. 4 , 387–392. https://doi.org/10.1038/ng0893-387 (1993). Kovtun, I. V., Therneau, T. M. & McMurray, C. T. Gender of the embryo contributes to CAG instability in transgenic mice containing a Huntington’s disease gene. Hum. Mol. Genet. 9 , 2767–2775. https://doi.org/10.1093/hmg/9.18.2767 (2000). Kovtun, I. V., Welch, G., Guthrie, H. D., Hafner, K. L. & McMurray, C. T. CAG repeat lengths in X- and Y-bearing sperm indicate that gender bias during transmission of Huntington’s disease gene is determined in the embryo. J. Biol. Chem. 279 , 9389–9391. https://doi.org/10.1074/jbc.M313080200 (2004). Nahhas, F., Garbern, J., Feely, S. & Feldman, G. L. An intergenerational contraction of a fully penetrant Huntington disease allele to a reduced penetrance allele: Interpretation of results and significance for risk assessment and genetic counseling. Am. J. Med. Genet. Part A 149a , 732–736. https://doi.org/10.1002/ajmg.a.32720 (2009). Tang, Y. et al. Intergeneration CAG expansion and contraction in a Chinese HD family. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 141b , 242–244. https://doi.org/10.1002/ajmg.b.30261 (2006). Article   CAS   Google Scholar   Wheeler, V. C. et al. Factors associated with HD CAG repeat instability in Huntington disease. J. Med. Genet. 44 , 695–701. https://doi.org/10.1136/jmg.2007.050930 (2007). Article   CAS   PubMed   PubMed Central   Google Scholar   Foroud, T., Gray, J., Ivashina, J. & Conneally, P. M. Differences in duration of Huntington’s disease based on age at onset. J. Neurol. Neurosurg. Psychiatry 66 , 52–56. https://doi.org/10.1136/jnnp.66.1.52 (1999). Genetic_Modifiers_of_Huntington’s_Disease_(GeM-HD)_Consortium. CAG repeat not polyglutamine length determines timing of Huntington’s disease onset. Cell 178 , 887-900.e814. https://doi.org/10.1016/j.cell.2019.06.036 (2019). Hentosh, S. et al. Sex differences in Huntington’s disease: Evaluating the enroll-HD database. Mov. Disord. Clin. Pract. 8 , 420–426. https://doi.org/10.1002/mdc3.13178 (2021). Roos, R. A. et al. Age at onset in Huntington’s disease: Effect of line of inheritance and patient’s sex. J. Med. Genet. 28 , 515–519. https://doi.org/10.1136/jmg.28.8.515 (1991). Kennedy, L. et al. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum. Mol. Genet. 12 , 3359–3367. https://doi.org/10.1093/hmg/ddg352 (2003). Gomes-Pereira, M. et al. Disease-associated CAG·CTG triplet repeats expand rapidly in non-dividing mouse cells, but cell cycle arrest is insufficient to drive expansion. Nucleic Acids Res. 42 , 7047–7056. https://doi.org/10.1093/nar/gku285 (2014). Gonitel, R. et al. DNA instability in postmitotic neurons. Proc. Natl. Acad. Sci. USA 105 , 3467–3472. https://doi.org/10.1073/pnas.0800048105 (2008). Article   ADS   PubMed   PubMed Central   Google Scholar   Swami, M. et al. Somatic expansion of the Huntington’s disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum. Mol. Genet. 18 , 3039–3047. https://doi.org/10.1093/hmg/ddp242 (2009). Manley, K., Shirley, T. L., Flaherty, L. & Messer, A. Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat. Genet. 23 , 471–473. https://doi.org/10.1038/70598 (1999). Pinto, R. M. et al. Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington’s disease mice: Genome-wide and candidate approaches. PLoS Genet. 9 , e1003930. https://doi.org/10.1371/journal.pgen.1003930 (2013). Genetic_Modifiers_of_Huntington’s_Disease_(GeM-HD)_Consortium. Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell 162 , 516–526. https://doi.org/10.1016/j.cell.2015.07.003 (2015). Goold, R. et al. FAN1 modifies Huntington’s disease progression by stabilizing the expanded HTT CAG repeat. Hum. Mol. Genet. 28 , 650–661. https://doi.org/10.1093/hmg/ddy375 (2019). Lee, J. M. et al. A modifier of Huntington’s disease onset at the MLH1 locus. Hum. Mol. Genet. 26 , 3859–3867. https://doi.org/10.1093/hmg/ddx286 (2017). Iyer, R. R. & Pluciennik, A. DNA mismatch repair and its role in Huntington’s disease. J. Huntingt. Dis. 10 , 75–94. https://doi.org/10.3233/jhd-200438 (2021). Kehoe, P., Krawczak, M., Harper, P. S., Owen, M. J. & Jones, A. L. Age of onset in Huntington disease: Sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J. Med. Genet. 36 , 108–111 (1999). CAS   PubMed   PubMed Central   Google Scholar   Snell, R. G. et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat. Genet. 4 , 393–397. https://doi.org/10.1038/ng0893-393 (1993). Aziz, N. A., van Belzen, M. J., Coops, I. D., Belfroid, R. D. & Roos, R. A. Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington’s disease. Eur. J. Med. Genet. 54 , e413-418. https://doi.org/10.1016/j.ejmg.2011.04.002 (2011). Article   PubMed   Google Scholar   Aziz, N. A. et al. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology 73 , 1280–1285. https://doi.org/10.1212/WNL.0b013e3181bd1121 (2009). Djoussé, L. et al. Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. Am. J. Med. Genet. Part A 119a , 279–282. https://doi.org/10.1002/ajmg.a.20190 (2003). Lee, J. M. et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 78 , 690–695. https://doi.org/10.1212/WNL.0b013e318249f683 (2012). Langbehn, D. R., Brinkman, R. R., Falush, D., Paulsen, J. S. & Hayden, M. R. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin. Genet. 65 , 267–277. https://doi.org/10.1111/j.1399-0004.2004.00241.x (2004). Langsrud, Ø. ANOVA for unbalanced data: Use type II instead of type III sums of squares. Stat. Comput. 13 , 163–167. https://doi.org/10.1023/a:1023260610025 (2003). Article   MathSciNet   Google Scholar   Saft, C. et al. Apolipoprotein E genotypes do not influence the age of onset in Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 75 , 1692–1696. https://doi.org/10.1136/jnnp.2003.022756 (2004). Shelbourne, P. F. et al. Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Hum. Mol. Genet. 16 , 1133–1142. https://doi.org/10.1093/hmg/ddm054 (2007). Telenius, H. et al. Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat. Genet. 6 , 409–414. https://doi.org/10.1038/ng0494-409 (1994). Larson, E., Fyfe, I., Morton, A. J. & Monckton, D. G. Age-, tissue- and length-dependent bidirectional somatic CAG ⋅ CTG repeat instability in an allelic series of R6/2 Huntington disease mice. Neurobiol. Dis. 76 , 98–111. https://doi.org/10.1016/j.nbd.2015.01.004 (2015). Hong, E. P. et al. Association analysis of chromosome X to identify genetic modifiers of Huntington’s disease. J. Huntingt. Dis. https://doi.org/10.3233/jhd-210485 (2021). Article   Google Scholar   Bode, F. J. et al. Sex differences in a transgenic rat model of Huntington’s disease: Decreased 17beta-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males. Hum. Mol. Genet. 17 , 2595–2609. https://doi.org/10.1093/hmg/ddn159 (2008). Nuzzo, M. T. et al. Huntingtin polyQ mutation impairs the 17β-estradiol/neuroglobin pathway devoted to neuron survival. Mol. Neurobiol. 54 , 6634–6646. https://doi.org/10.1007/s12035-016-0337-x (2017). Jedrak, P. et al. Mitochondrial DNA levels in Huntington disease leukocytes and dermal fibroblasts. Metab. Brain Dis. 32 , 1237–1247. https://doi.org/10.1007/s11011-017-0026-0 (2017). DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277 , 1990–1993. https://doi.org/10.1126/science.277.5334.1990 (1997). Farrer, L. A. et al. The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD. Am. J. Hum. Genet. 53 , 125–130 (1993). Download references Acknowledgements We would like to thank all EHDN REGISTRY Study Group Investigators who collected the data and all participating REGISTRY patients. The list of  REGISTRY investigators of the European Huntington’s Disease Network is included in the Supplementary Information . Supported by data mining project 636 from the European Huntington Disease Network (EHDN) and CHDI Foundation, Inc. The funders had no role in data analysis, decision to publish, or manuscript preparation. Author information A list of authors and their affiliations appears at the end of the paper. Authors and Affiliations Department of Biotechnology and Microbiology, Gdańsk University of Technology, 80-233, Gdańsk, Poland Anna Stanisławska-Sachadyn Department of Biology and Medical Genetics, Medical University of Gdańsk, 80-211, Gdańsk, Poland BioTechMed Center, Gdańsk University of Technology, Narutowicza 11/12, 80-233, Gdańsk, Poland Institute of Applied Mathematics , Gdańsk University of Technology, 80-233, Gdańsk, Poland Michał Krzemiński Department of Public Health, Poznań University of Medical Sciences, 60-812, Poznan, Poland Daniel Zielonka Department of Developmental Neurology, Medical University of Gdansk, 80-952, Gdańsk, Poland Magdalena Krygier Institute of Human Genetics, Polish Academy of Sciences, 60-479, Poznan, Poland Ewa Ziętkiewicz Department of Neurology, St. Adalbert Hospital, Copernicus PL, 80-462,, Gdańsk, Poland Jarosław Sławek Department of Neurological and Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdańsk, 80-211, Gdańsk, Poland Department of Medical Ethics, Medical University of Gdańsk, 80-211, Gdańsk, Poland Janusz Limon You can also search for this author in PubMed   Google Scholar  & Jarosław Sławek Contributions A. S-S. designed and conceptualized study, organized data, designed and executed statistical analyses, wrote first paper draft; M. K. performed the statistical analyses; D. Z. interpreted results, designed and critiqued statistical analyses, substantively revised the work; M. Kry. reviewed and critiqued the manuscript; E. Z. designed and critiqued statistical analyses, interpreted results, revised the work and edited it; J. S. designed and conceptualized study, substantively revised the work; and J. L. substantively revised the work. All authors read and approved the final manuscript. Corresponding author Correspondence to Anna Stanisławska-Sachadyn . Ethics declarations Competing interests. The authors declare no competing interests. Additional information Publisher's note. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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Reprints and permissions About this article Cite this article. Stanisławska-Sachadyn, A., Krzemiński, M., Zielonka, D. et al. Sex contribution to average age at onset of Huntington’s disease depends on the number of (CAG) n repeats. Sci Rep 14 , 15729 (2024). https://doi.org/10.1038/s41598-024-64105-5 Download citation Received : 22 December 2023 Accepted : 05 June 2024 Published : 08 July 2024 DOI : https://doi.org/10.1038/s41598-024-64105-5 Share this article Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative By submitting a comment you agree to abide by our Terms and Community Guidelines . If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. 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Search in PubMed Search in NLM Catalog Add to Search Clinical Features of Huntington's Disease Affiliations. 1 UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK. 2 UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK. [email protected]. PMID: 29427096 DOI: 10.1007/978-3-319-71779-1_1 Huntington's disease (HD) is the most common monogenic neurodegenerative disease and the commonest genetic dementia in the developed world. With autosomal dominant inheritance, typically mid-life onset, and unrelenting progressive motor, cognitive and psychiatric symptoms over 15-20 years, its impact on patients and their families is devastating. The causative genetic mutation is an expanded CAG trinucleotide repeat in the gene encoding the Huntingtin protein, which leads to a prolonged polyglutamine stretch at the N-terminus of the protein. Since the discovery of the gene over 20 years ago much progress has been made in HD research, and although there are currently no disease-modifying treatments available, there are a number of exciting potential therapeutic developments in the pipeline. In this chapter we discuss the epidemiology, genetics and pathogenesis of HD as well as the clinical presentation and management of HD, which is currently focused on symptomatic treatment. The principles of genetic testing for HD are also explained. Recent developments in therapeutics research, including gene silencing and targeted small molecule approaches are also discussed, as well as the search for HD biomarkers that will assist the validation of these potentially new treatments. Keywords: Biomarkers; Genetics; Huntington’s disease; Management; Symptoms; Therapeutics. PubMed Disclaimer Similar articles Huntington's Disease: Relationship Between Phenotype and Genotype. Sun YM, Zhang YB, Wu ZY. Sun YM, et al. Mol Neurobiol. 2017 Jan;54(1):342-348. doi: 10.1007/s12035-015-9662-8. Epub 2016 Jan 7. Mol Neurobiol. 2017. PMID: 26742514 Review. Huntington's disease: clinical presentation and treatment. Novak MJ, Tabrizi SJ. Novak MJ, et al. Int Rev Neurobiol. 2011;98:297-323. doi: 10.1016/B978-0-12-381328-2.00013-4. Int Rev Neurobiol. 2011. PMID: 21907093 Review. Huntington's disease: a clinical review. McColgan P, Tabrizi SJ. McColgan P, et al. Eur J Neurol. 2018 Jan;25(1):24-34. doi: 10.1111/ene.13413. Epub 2017 Sep 22. Eur J Neurol. 2018. PMID: 28817209 Review. Immunomodulatory Strategies for Huntington's Disease Treatment. Colpo GD, Rocha NP, Stimming EF, Teixeira AL. Colpo GD, et al. CNS Neurol Disord Drug Targets. 2017;16(8):936-944. doi: 10.2174/1871527316666170613084801. CNS Neurol Disord Drug Targets. 2017. PMID: 28606048 Review. Clinical Aspects of Huntington's Disease. Ghosh R, Tabrizi SJ. Ghosh R, et al. Curr Top Behav Neurosci. 2015;22:3-31. doi: 10.1007/7854_2013_238. Curr Top Behav Neurosci. 2015. PMID: 23975844 Review. Identification of molecular targets and small drug candidates for Huntington's disease via bioinformatics and a network-based screening approach. Hossain MR, Tareq MMI, Biswas P, Tauhida SJ, Bibi S, Zilani MNH, Albadrani GM, Al-Ghadi MQ, Abdel-Daim MM, Hasan MN. Hossain MR, et al. J Cell Mol Med. 2024 Aug;28(16):e18588. doi: 10.1111/jcmm.18588. J Cell Mol Med. 2024. PMID: 39153206 Free PMC article. Gastrodin Improves the Activity of the Ubiquitin-Proteasome System and the Autophagy-Lysosome Pathway to Degrade Mutant Huntingtin. Sun H, Li M, Li Y, Zheng N, Li J, Li X, Liu Y, Ji Q, Zhou L, Su J, Huang W, Liu Z, Liu P, Zou L. Sun H, et al. Int J Mol Sci. 2024 Jul 14;25(14):7709. doi: 10.3390/ijms25147709. Int J Mol Sci. 2024. PMID: 39062952 Free PMC article. Neuroimaging to Facilitate Clinical Trials in Huntington's Disease: Current Opinion from the EHDN Imaging Working Group. Hobbs NZ, Papoutsi M, Delva A, Kinnunen KM, Nakajima M, Van Laere K, Vandenberghe W, Herath P, Scahill RI. Hobbs NZ, et al. J Huntingtons Dis. 2024;13(2):163-199. doi: 10.3233/JHD-240016. J Huntingtons Dis. 2024. PMID: 38788082 Free PMC article. Review. Neuroinflammation and the role of epigenetic-based therapies for Huntington's disease management: the new paradigm. Temgire P, Arthur R, Kumar P. Temgire P, et al. Inflammopharmacology. 2024 Jun;32(3):1791-1804. doi: 10.1007/s10787-024-01477-0. Epub 2024 Apr 23. Inflammopharmacology. 2024. PMID: 38653938 Review. Striatal insights: a cellular and molecular perspective on repetitive behaviors in pathology. Burton CL, Longaretti A, Zlatanovic A, Gomes GM, Tonini R. Burton CL, et al. Front Cell Neurosci. 2024 Mar 27;18:1386715. doi: 10.3389/fncel.2024.1386715. eCollection 2024. Front Cell Neurosci. 2024. PMID: 38601025 Free PMC article. Review. Publication types Search in MeSH Related information PubChem Compound (MeSH Keyword) Grants and funding 200181/Z/15/Z/WT_/Wellcome Trust/United Kingdom MR/K023268/1/MRC_/Medical Research Council/United Kingdom MR/L012936/1/MRC_/Medical Research Council/United Kingdom LinkOut - more resources Full text sources, other literature sources. scite Smart Citations MedlinePlus Health Information Citation Manager NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited. An official website of the United States government The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site. The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. Publications Account settings The PMC website is updating on October 15, 2024. Learn More or Try it out now . Advanced Search Journal List Dialogues Clin Neurosci v.18(1); 2016 Mar Language: English | Spanish | French Huntington disease: a single-gene degenerative disorder of the striatum Enfermedad de huntington: un trastorno degenerativo monogénico del estriado, la maladie de huntington : une affection dégénérative monogénique du striatum, peggy c. nopoulos. Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA Huntington disease (HD) is an autosomal dominant, neurodegenerative disorder with a primary etiology of striatal pathology. The Huntingtin gene (HTT) has a unique feature of a DNA trinucleotide (triplet) repeat, with repeat length ranging from 10 to 35 in the normal population. Repeat lengths between 36 and 39 cause HD at reduced penetrance (some will get the disease, others won't) and when expanded to 40 or more repeats (mHTT), causes HD at full penetrance (every person with this length or beyond will definitely develop the disease). The symptoms of HD may be motor, cognitive, and psychiatric, and are consistent with the pathophysiology of frontostriatal circuitry malfunction. Expressed ubiquitously and throughout the entire life cycle (development through adulthood), mHTT causes initial dysfunction and eventual death of a specific cell population within the striatum. Although all areas of the brain are eventually affected, the primary pathology of the disease is regionally specific. As a single-gene disorder, HD has the distinction of having the potential of treatment that is aimed directly at the known pathogenic mechanism by gene silencing, providing hope for neuroprotection and ultimately, prevention. La Enfermedad de Huntington (EH) es un trastorno neurodegenerativo autosómico dominante con una etiología primaria de la patología estriatal. El gen de la proteína huntingtina (HTT) tiene una característica distintiva cual es la repetición del trinucleótido de DNA (triplete), con una longitud de repetición que va de 10 a 35 veces en la población normal. Las longitudes de repetición entre 36 y 39 veces provocan una EH de pene-tración reducida (algunos adquirirán la enfermedad y otros no) y cuando se expanden a 40 o más repeticiones (mHTT), se provoca la EH de penetración completa (cada persona con esta longitud o más desarrollará definitivamente la enfermedad). Los síntomas de la EH pueden ser motores, cognitivos y psiquiátricos y son consistentes con la fisiopatología de un mal funcionamiento del circuito fronto-estriatal. El mHTT provoca una disfunción inicial y la eventual muerte de una población celular específica dentro del estriado, al expresarse de manera ubicua y durante toda la vida (con un desarrollo en la adultez). Aunque todas las áreas del cerebro están eventualmente afectadas, la patología primaria de la enfermedad ocurre en una región específica. Como un trastorno monogénico, la EH se distingue por tener una terapéutica potencial dirigida directamente al mecanismo patogénico conocido como el silenciamiento génico, dando esperanzas de neuroprotección y finalmente de prevención. La maladie de Huntington (MH) est une affection neu-rodégénérative autosomique dominante dont l'étiologie primaire est une maladie du striatum. Le gène de la protéine Huntingtine (HTT) se présente sous la forme particulière d'une répétition d'un trinucléotide de l'ADN (triplet), la longueur de la répétition variant de 10 à 35 fois dans la population normale. Des longueurs répétées entre 36 et 39 fois provoquent une MH à pénétrance réduite (certains auront la maladie, d'autres non) et des répétitions de 40 fois et plus (HTTm) entraînent une MH à pénétrance complète (chaque personne porteuse de cette longueur et au-delà développera la maladie de façon certaine). Les symptômes de la MH peuvent être moteurs, cognitifs et psychiatriques et concordent avec la physiopathologie d'une dysfonction du circuit striato-frontal. Exprimé de façon ubiquitaire et tout au long d'une vie entière (il se développe pendant toute la vie adulte), le gène HTTm est responsable de la dysfonction initiale et de la mort finale d'une population cellulaire spécifique dans le striatum. Toutes les zones cérébrales sont finalement touchées mais la pathologie primaire de la maladie est spécifique localement. En tant qu'affection monogénique, la MH a la particularité de pouvoir bénéficier d'un traitement dirigé directement contre le mécanisme pathogène connu par silençage génique, ce qui est porteur d'espoir pour la neuroprotection et enfin pour la prévention. Introduction Huntington disease (HD) is an autosomal dominant, neurodegenerative disorder with a primary etiology of corticostriatal pathology. HD is caused by a DNA trinucleotide (triplet) repeat expansion of equal to or greater than 40 CAG repeats within the gene Huntingtin (HTT, OMIM 613004). Repeat numbers vary from 6 to 35 in the general population. When there are less than 27 repeats, there is no manifestation of HD, and the gene is stable upon transmission. Repeat lengths in the range of 27 to 35 also are not associated with development of HD; however, there is a possibility of expansion upon transmission, giving rise to the phenomenon of genetic anticipation. Expansion upon transmission is more likely at longer repeat lengths within this range, and is also more likely to happen during male transmission. 1 CAG repeats in the range of 36 to 39 are of incomplete penetrance with variable disease manifestation. Phenomenology HD is a rare disease with a prevalence of approximately 10 to 12 individuals per 100 000 of European ancestry. 2 The number of repeats in HTT is inversely associated with disease onset such that the greater the number, the earlier the onset. 3 Onset of disease is defined as manifestation of significant motor or neurologic symptoms and occurs on average around the age of 40. Although the number of repeats in HTT accounts for roughly 50% to 70% of the variance in age of onset, 4 there remain other influential factors yet to be defined; these are likely to be environmental elements or modifying gene factors. Although repeat length does not account for all of the variance in age of onset, the strong relationship allows for some generalizations. ( Figure 1 ). displays the general relationship between age of onset and CAG repeat number. Those with later onset are more likely to have fewer repeats, sometimes in the intermediate range. Classic adult onset between the ages of 30 and 50 are associated with repeat lengths between 40 and 49. Repeat lengths larger than 50 are typically associated with onset between 20 and 30 years of age. When disease onset occurs prior to the age of 21, it is referred to as juvenile HD (JHD), which constitutes about 5% of all HD cases. 5 Within JHD, repeat lengths greater than 60 are associated with age of onset between 10 and 20, and the very highest repeat numbers — over 80 — can manifest in childhood onset, where the diagnosis is made before the age of 10. The earliest reported diagnosis was in an 18-month-old with a repeat length over 200 . 6 The course of disease in HD is relatively long compared with other neurodegenerative disorders, lasting on average 15 years from diagnosis to death. Although the CAG repeat number is highly correlated with age of onset, it does not appear to have much impact on length of disease, suggesting that once the disease process begins, other factors determine course of disease rather than the length of the mutation. Stages of HD can be categorized based on the patient's functional capacity, which is expressed as a standardized scale. 7 The Shoulson-Fahn staging system ranges from stage 1 through stage 5 with the earliest stage having full functional capacity (early in the disease) and stage 5, severely limited functional capacity. Patients in stage 5 typically need total care and are most often in a nursing home. Sine the discovery of the gene in 1993, it is possible to test persons who are at risk for HD (due to autosomal dominance, each child of a parent with HD has a 50% chance of inheriting the mutation). In terms of clinical aspects, at the age of 18 has been persons at risk can undergo presymptomatic testing to find out if they do indeed carry the mutant gene. This is a choice that relatively few people at risk (roughly 5% to 10%) choose to make, and it requires a multi visit protocol with genetic counselors, neurologists, and often a psychiatrist or psychologist. Clinical symptoms The clinical symptoms of HD are classically defined as occurring in three domains: motor, cognitive, and psychiatric. The motor symptoms are progressive and—early in the disease—are mostly hyperkinetic with involuntary movements of chorea. These movements generally begin distally and are of small degree, then become more axial and are of greater amplitude. Movements are often incorporated into natural voluntary movements and, thus, early on may appear as simple restlessness. Although the early stages of motor symptoms are hyperkinetic, in later stages of the disease, motor symptoms tend to be hypokinetic with bradykinesia and dystonia. 8 Other classic symptoms are motor impersistence and abnormal eye movements. Late in the disease, dysphagia becomes a symptom with high morbid impact, as aspiration is a common occurrence, and pneumonia is a common cause of death. Cognitive dysfunction occurs in the vast majority of patients. In early stages, this can be somewhat limited to executive function, with difficulties in decision making, organization, planning, and multitasking. Eventually, these symptoms progress, and a more global picture of cognitive deficits emerges with an ultimate diagnosis of dementia. In general, the dementia of HD is considered to be “subcortical,” highlighting the involvement of the corticostriatal pathways. Key differences between HD dementia and a classic cortical dementia is that, in memory tasks, patients with HD can recall items better if cued, suggesting that it involves an inefficient search of memory rather than a deficient memory per se. In general, memory loss occurs later in HD, and problems that are typical of cortical dementias, such as aphasia and apraxia, are not as common in HD. Importantly, the cognitive deficits in HD may precede the motor symptoms by many years. It is not uncommon in a clinical setting to have a formal clinical diagnosis of HD made for the first time based on motor abnormality though the cognitive deficits have already reached the level of dementia. Psychiatric symptoms associated with HD can span a variety of domains; however, the most common symptoms are consistent with frontal lobe dysfunction, in line with the known pathophysiology of the disease. 9 Initially, these symptoms are in the domain of frontal disinhibition, with symptoms of poor attention, irritability, impulsivity, and poor mood regulation. Early in the disease course, family members often conceptualize such symptoms as a personality change. The irritability associated with HD can be severe, and results in outbursts of anger and aggression, with prevalence recently reported as being as high as between 22% and 66% of patients. 10 Later in the disease, the symptoms often take on more of a frontal abulic constellation of symptoms, with prominent apathy or loss of initiative, creativity, and curiosity. This is accompanied by pervasive emotional blandness. Family members often interpret these symptoms as depression, and objectively, the patient certainly appears more withdrawn, uninterested, and noninteractive. However, subjectively, patients will deny any feelings of sadness or hopelessness and typically describe their mood as fine or good. These frontal lobe symptoms (disinhibition and abulia) of HD are a likely manifestation of the frontostriatal pathology of degeneration. Apathy is, in general, the most common feature of the disease, occurring at the highest prevalence and is progressive, 11 tracking along with other progressive features such as motor symptoms and cognitive decline. Depression is a feature that is commonly reported to be associated with HD. 12 However, what is not clear is whether depressive symptoms are a manifestation of the disease process with direct connections to the neural underpinnings of pathology. Importantly, the course of depressive symptoms is opposite what one would expect if these symptoms were core features that were directly linked to the pathophysiology of the degenerative process. That is, depression is most common at early points in the illness—the first period is right around the time of diagnosis, and the second is during stage 2 when some impairment begins to hamper function. 13 However, from this point on, depressive symptoms appear to decline in prevalence. Parallel with this time course is risk of suicide, which is highest near the time of diagnosis and which then drops off and diminishes after that. 14 Given the course of a degenerative disease, any associated symptom that is present early in the course of disease but lessens with time suggests that it is not the underlying pathology leading to depressive symptoms. It may well be that the increase in depressive symptoms occurring early in the course of disease may be due to an appropriate psychological reaction to the stressors of dealing with either the knowledge or the emergence of a fatal brain disease. Despite the etiology of depressive symptoms in HD, the treatment of these symptoms and the need for careful screening of suicide risk remains a vital part of the care of this patient population. A prominent feature of HD is lack of awareness or lack of insight into the nature or severity of symptoms that the patient is experiencing. This can include lack of awareness of any feature of the disease, including all three domains of motor, cognitive, or behavioral symptoms. 16 , 15 This feature makes it important to consider family members as helpful (sometime crucial) sources of information who provide objective appraisals of the patient's symptoms and level of function, and they should be involved in the patient's health care assessments and decision making. The gene HTT is but one in a class of genes in which a CAG repeat (triplet coding for glutamine, represented as Q) is present, which when expanded causes brain disease. These can be classified as the polyQ (meaning repeating glutamine) diseases and include spinocerebellar ataxia (of which there are several types), dentatorubropallidoluysian atrophy (DRPLA) and spinal and bulbar muscular atrophy (SBMA). All polyQ diseases share the features of being autosomal dominant and causing disease when the number of CAG repeats crosses a certain threshold. Beyond polyQ diseases, there are several other diseases that are caused by triplet repeat, and these include fragile X syndrome (CGG repeat), Friedreich ataxia (GAA repeat), and myotonic dystrophy (CTG repeat). Although a lot of work has been done on the study of the expanded or mutant form of HTT (mHTT), there has been relatively little work on understanding the normal gene and its function. 17 Some of this is due to the large size of the huntingtin protein (making isolation difficult), the fact that it is located everywhere in the body (ubiquitous expression), and that, within the cell, it interacts with more than 200 partners/proteins. 18 What is known is that like other homopeptide-repeatcontaining proteins, huntingtin functions by creating m ul ti protein complex form at ions. The actual function is not clear and may vary, but reports support functions in transcriptional regulation, nucleocytoplasmic shuttling, synaptic function, and antiapoptic activity. 19 It is also known that HTT is a highly conserved gene. However, the CAG repeats in the gene are not conserved. Work by Tatari et al 20 demonstrated that phylogenetic comparison of HTT homologs reveal the appearance of repeats first in deuteros tomes, and the repeats then increase — the more evolved the species, the greater the number of repeats, with humans having the highest number. For this and a number of reasons, it has been postulated thaXHTT, and possibly other genes like it, may have an important role in the evolution of the brain from primate to human. 21 In terms of mHTT and the disease process, the conundrum is that, despite ubiquitous expression throughout the entire body and from conception through adulthood, the primary site of pathology is specific to the striatum. Even more specific is the type of neuron that is most vulnerable. Striatal GABAergic spiny projection neurons (SPNs) come in two types, as follows: indirect pathway SPNs (iSPNs), which suppress inappropriate movements, and direct pathway SPNs (dSPNs), which promote appropriate movements. It is the iSPNs that are affected first and are consistent with the manifestation of chorea as the presenting motor abnormality. Later in the disease, dSPNs are affected, leading to the hypokinetic motor symptoms of later-stage disease. Most recent evidence points to the pathophysiology of mHTT being the impairment of cortical pyramidal neurons to provide the striatum with needed brain derived neurotrophic factor (BDNF). 22 , 23 This has been said to lead to the ”withering“ of the striatal cells. Although eventually all regions and tissues of the brain are affected, the disease process is clearly selective and specific to the striatum. Another major theme in the research on etiology of HD is the disturbance of cell metabolism. Biochemical studies have shown disrupted metabolic processes of post-mortem HD brains 24 and lymphoblast cell lines of HD patients. 25 Impaired energetics in HD were not limited to neuronal tissues and were also found in HD adult skeletal muscles, 26 - 28 implying an integral role for huntingtin in mitochondrial energy metabolism. This disturbance in metabolism has been linked clinically to the symptoms of lower weight and body mass index (BMI) in patients with HD. This has been shown to be independent of the amount of chorea that is present, and in later stages of the disease, it can lead to cachexia. More importantly, low BMI is present in preHD subjects and points to an energy imbalance that may be primary to the disease process. 29 , 30 The role of abnormal development In general, HD is classically conceptualized as a neurodegenerative disease of the striatum. However, multiple lines of evidence support the theory that abnormal brain development may play an important role in the etiology of HD, as well as other degenerative brain disorders. Abnormal development and degeneration are not mutually exclusive. There is no doubt that HD is a neurodegenerative disorder. However, persuasive work in molecular biology has supported the theory of neurodevelopmental mechanisms of degeneration. This theory suggests that neurodegenerative diseases such as Alzheimer disease and HD may represent a novel class of developmental disorders in which subsets of neural populations are vulnerable because of abnormal development, and exist in a mutant steady state before succumbing to environmental stressors or toxins that normally would not promote cell death. 31 Huntingtin and development Normal HTT is necessary for brain development; embryos of HTT knock-out mice have major abnormalities in central nervous system development and die shortly after birth. 32 It is also known that HTT is expressed in the brain throughout development 33 , 34 and plays a vital role in neuronal survival and stability. 35 Therefore, given HTTs key role in development, a partial loss of function may manifest in abnormal neural development. Although the classic theory of HD etiology is that mutant HTT (mHTT) results in a gain-of-function toxicity that results in neural damage, there is also compelling evidence that in addition to this mechanism, loss of function of normal HTT may also be an important mechanism in the disease. 17 , 36 More recent work by Nguyen et al 37 has shown that HTT is essential for the program of neural induction, progressive specification of neural progenitor cell types, and the subsequent elaboration of neural lineage species. Moreover, mHTT was shown to cause impairments in multiple stages of striatal development, supporting the notion that the selective vulnerability of striatal neurons may have a developmental etiology. 37 One of the benefits of the HTT gene discovery was the opportunity it afforded to study presymptomatic HD subjects, also known as preHD. This allows the measurement of brain structure and function in people who are years from the onset of disease. One large multisite study with more than 1300 at-risk adults enrolled has shown that preHD subjects exhibit abnormalities in brain structure, cognition, behavior, and motor function long before (up to 20 years) a clinical diagnosis is made. 9 , 38 - 46 Multiple other studies, both large and small, have also found abnormalities in preHD adults decades before onset. 47 - 51 Some have suggested that these changes are due to early degeneration. 52 - 54 However, an alternate explanation is that these subtle symptoms are manifestations of abnormal brain development and are present throughout life. If it is true that HD has a vital portion of its pathophysiology based in abnormal development, a conceptual shift in our understanding of this disease (and other degenerative disorders) will be in order. The current etio logic dogma of HD is that the disease process lies within the toxic effects of mutant huntingtin (encoded by mHTT), which accumulates in the cell, is toxic, and causes degeneration. An alternative theory is that HTTs vital role in development is compromised in the mHTT form, leading to abnormal development, which is, in and of itself, part of the disease process. This mutant neuronal circuit is initially able to compensate and remain relatively functional, though with subtle abnormalities (mutant steady state). Later, maturation and aging processes (and toxic effects of mutant huntingtin) eventually tip the faulty circuit toward degeneration. A schematic of the model is shown in ( Figure 2 ). Evidence of abnormal brain development in human research includes one large magnetic resonance imaging study showing that pre-HD males had smaller intracranial volumes (ICV) than healthy controls. 40 ICV is a proxy measure of maximum brain growth during development; therefore, lower ICV is indicative of poor general brain growth. Also, a unique study of children at risk for HD has shown that children who are preHD (average age 12) have lower BMI and smaller head circumference values than healthy controls, again supporting the notion that abnormal growth may be a vital part of the pathologic process in HD. 55 Juvenile Huntington disease Longer expansions of HTT cause early onset of the disease. When this occurs prior to age 21, it is termed JHD. JHD is similar to adult-onset HD in many ways, with the same triad of motor, cognitive, and psychiatric symptoms. However, one distinct difference is the presentation and predominance of motor symptoms: In adult-onset HD, early motor symptoms are chorea/hyperkinetic and later on, hypokinetic. In JHD, the motor presentation is typically hypokinetic with bradykinesia/ stiffness/dystonia and may become hyperkinetic later in the disease. 56 One other accompanying feature that is somewhat unique to JHD is seizures. Most common in childhood-onset JHD (diagnosed before the age of 10), seizures can be severe and difficult to treat. 57 The cognitive changes in JHD are progressive but, in the context of children, may also affect their ability to learn and obtain skills before degeneration of those skills occurs. Of the symptoms of JHD, the psychiatric and behavioral symptoms are far more consistent and prominent. That is, most patients will have behavioral symptoms. In one large study, 70% of JHD subjects presented with behavioral symptoms; during the course of disease, 93% of males and 81% of females experienced psychiatric issues. 58 These symptoms are made up almost exclusively of externalizing behaviors of hyperactivity, impulsivity, poor mood regulation, irritability, and anger outbursts. Although there is a perception that JHD patients may have a more rapid disease course than those with adult onset, the literature has conflicting reports, leaving it a question that has yet to be fully explored. 56 Gene therapy By far the most exciting and promising advances in research on HD have been made in the work toward treatment with gene therapy. A potential therapeutic for dominant genetic disorders, silencing of mutant genes provides the opportunity for treatment with major impact. In general, the promise of gene therapy could be twofold: (i) restoration of function by returning to health neuronal circuits that are not yet dead, but dysfunctional and (ii) neuroprotection with a lack of disease progression. In fact, the ultimate use of gene therapy would not be in treatment, but in prevention of disease — avoidance of symptoms entirely. The approaches of gene therapy are based on targeting the processes of DNA information being copied into messenger RNA or mRNA (a process called transcription) and on the synthesis of proteins using the information in mRNA (a process called translation). Gene-silencing techniques have three general approaches, as follows: repression of transcription using zinc finger proteins, repression of translation of mHTT by antisense oligonucleotides (ASOs), and blocking protein translation using RNA interference techniques. 59 The large neuroimaging studies done in preHD and early-stage patients have shown that quantitative measures of brain regions such as the striatum are excellent biomarkers of disease progression and will be useful in the context of the upcoming gene therapy studies. 42 , 60 , 61 HD, a single-gene degenerative disorder of the striatum, has seen more than two decades of intense research, spurred by the identification of the gene in 1993. This research has led to a better understanding of the pathoetiology of the disease; however, there is much still to be studied, especially in the context of understanding the role of abnormal development. In addition, very little is known about the normal function of HTT, which is vital to brain development. Despite these areas of uncertainty, much progress has been made, particularly regarding the promise, and now reality, of new methods of treatment and potential prevention in the context of gene therapy approaches. 396 COMMENTS Current and Possible Future Therapeutic Options for Huntington's Disease Keywords: chorea, antipsychotic medication, antidepressants, mood stabilizers, antisense oligonucleotides, RNAi therapies, Huntington's disease. HD is an autosomal dominant neurodegenerative disease that currently has no approved cure. HD is characterized by an increased number of CAG trinucleotide repeats in the huntingtin gene () on the ... Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Huntington's disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. ... Huntington's Disease Collaborative Research Group. 1993. A novel ... Prevalence and Incidence of Huntington's Disease: An Updated Systematic Huntington's disease (HD) is a neurodegenerative condition with a wide neuropsychiatric clinical spectrum that may involve different combinations of movement disorders (primarily chorea), dementia, and behavioral or psychiatric manifestations. 1 HD is a polyglutamine disease caused by a CAG trinucleotide repeat expansion in the huntingtin gene (HTT), located on chromosome 4. Huntington's disease Huntington's disease is a hereditary neurodegenerative disorder caused by an autosomal dominant mutation. The hallmark symptom of Huntington's disease is the presence of progressive chorea ... Huntington's disease: a clinical review Abstract. Huntington's disease (HD) is a fully penetrant neurodegenerative disease caused by a dominantly inherited CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. In Western populations HD has a prevalence of 10.6-13.7 individuals per 100 000. It is characterized by cognitive, motor and psychiatric disturbance. Huntington's disease: a clinical review Huntington's disease (HD) is a fully penetrant neurodegenerative disease caused by a dominantly inherited CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. ... Search for more papers by this author. P. McColgan, P. McColgan. Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology ... Huntington's disease: diagnosis and management Huntington's disease (HD) is an inherited neurodegenerative disease characterised by neuropsychiatric symptoms, a movement disorder (most commonly choreiform) and progressive cognitive impairment. ... 5 Wellcome Trust Medical Research Council - Cambridge Stem Cell Institute, Cambridge, UK. PMID: 34413240 DOI: 10.1136/practneurol-2021-003074 ... Huntington's disease: from molecular pathogenesis to clinical ... Nuclear Proteins. Peptides. polyglutamine. Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which encodes an abnormally long polyglutamine repeat in the huntingtin protein. Huntington's disease has served as a model for the study of other more common neurodegene …. New Avenues for the Treatment of Huntington's Disease Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. ... Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial ... Recent approaches on Huntington's disease (Review) 2. Genetics and pathology of Huntington's disease. HD is a fatal, autosomal dominant, progressive neurodegenerative disorder characterized by severe symptoms, including motor, cognitive and psychiatric symptoms, atrophy of the basal ganglia and the cerebral cortex, and an inevitably progressive course, resulting in mortality 5-20 years following the manifestation of symptoms. Huntington disease: Advances in the understanding of its mechanisms Abstract. Huntington disease (HD) is a devastating monogenic autosomal dominant disorder. HD is caused by a CAG expansion in exon 1 of the gene coding for huntingtin, placed in the short arm of chromosome 4. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. Targeting Huntingtin Expression in Patients with Huntington's Disease Huntington's disease is a progressive neurodegenerative disorder inherited as an autosomal-dominant trait, with onset typically occurring in mid-adult life and characterized by movement disorder ... Prevalence and Incidence of Huntington's Disease: An Updated ... Abstract. The incidence and prevalence of Huntington's disease (HD) based on a systematic review and meta-analysis of 20 studies published from 1985 to 2010 was estimated at 0.38 per 100,000 person-years (95% confidence interval [CI], 0.16-0.94) and 2.71 per 100,000 persons (95% CI, 1.55-4.72), respectively. Since 2010, there have been many new ... Review of Huntington's Disease: From Basics to Advances in Diagnosis Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder with complete penetrance caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin (HTT) gene (previously called IT-15) on chromosome 4.The expanded CAG results in a mutant protein (huntingtin (HTT)) rich in glutamine amino acids (polyQ), with toxic properties to the cell. Huntington's Disease: A Clinical Review Abstract. The Huntington's gene on chromosome 4 has a dominantly inherited CAG trinucleotide repeat expansion, ultimately resulting in Huntington's disease (HD), a completely penetrant neurological condition. The frequency is 10-100 times higher in the population descended from Europe than in East Asia. Through various processes, including ... (PDF) Huntington's Disease: A Clinical Review Step 1 Clinical genetics consultation, idea lly in conjunction with a psychiatrist and a neurologist. Step 2 A second session that includes a b lood sample is held four to six week s later. Step 3 ... (PDF) Huntington's disease: A clinical review Abstract and Figures. Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric ... The Neuropsychology of Huntington's Disease Neuropsychology. Huntington's disease is an inherited, degenerative brain disease, characterized by involuntary movements, cognitive disorder and neuropsychiatric change. Men and women are affected equally. Symptoms emerge at around 40 years, although there is wide variation. A rare juvenile form has onset in childh …. Review of Huntington's Disease: From Basics to Advances in Diagnosis We conducted the present review facing the enormous growth of scientific knowledge in Huntington's disease (HD) and the need for a practical update for general neurologists. HD is a devastating neurodegenerative disease of autosomal dominant inheritance and full penetrance, caused by an expansion of the cytosine-adenine-guanine (CAG ... Huntington's disease: a clinical review Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. Sex contribution to average age at onset of Huntington's disease Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the extension of the CAG repeats in exon 1 of the HTT gene and is transmitted in a dominant manner. The present ... Clinical Features of Huntington's Disease Abstract. Huntington's disease (HD) is the most common monogenic neurodegenerative disease and the commonest genetic dementia in the developed world. With autosomal dominant inheritance, typically mid-life onset, and unrelenting progressive motor, cognitive and psychiatric symptoms over 15-20 years, its impact on patients and their families is ... Huntington disease: a single-gene degenerative disorder of the striatum Huntington disease (HD) is an autosomal dominant, neurodegenerative disorder with a primary etiology of corticostriatal pathology. HD is caused by a DNA trinucleotide (triplet) repeat expansion of equal to or greater than 40 CAG repeats within the gene Huntingtin OMIM 613004). Repeat numbers vary from 6 to 35 in the general population. assignment essay homework paper phd report resume review thesis