Skip to main content

Advertisement

SpringerLink
Log in

Huntington’s disease: the coming of age

  • Review Article
  • Published:
Journal of Genetics Aims and scope Submit manuscript

Abstract

Huntington’s disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes abnormalities in the functioning of protein, leading to deleterious effects ultimately to the demise of specific neuronal cells. The disease is inherited in an autosomal dominant manner and leads to a plethora of neuropsychiatric behaviour and neuronal cell death mainly in striatal and cortical regions of the brain, eventually leading to death of the individual. The discovery of the mutant gene led to a surge in molecular diagnostics of the disease and in making different transgenic models in different organisms to understand the function of wild-type and mutant proteins. Despite difficult challenges, there has been a significant increase in understanding the functioning of the protein in normal and other gain-of-function interactions in mutant form. However, there have been no significant improvements in treatments of the patients suffering from this ailment and most of the treatment is still symptomatic. HD warrants more attention towards better understanding and treatment as more advancement in molecular diagnostics and therapeutic interventions are available. Several different transgenic models are available in different organisms, ranging from fruit flies to primate monkeys, for studies on understanding the pathogenicity of the mutant gene. It is the right time to assess the advancement in the field and try new strategies for neuroprotection using key pathways as target. The present review highlights the key ingredients of pathology in the HD and discusses important studies for drug trials and future goals for therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Adachi Y. and Nakashima K. 1999 Population genetic study of Huntington’s disease-prevalence and founder’s effect in the San-in area, western Japan. Nippon Rinsho. 57, 900–904.

    PubMed  CAS  Google Scholar 

  • Albin R. L., Reiner A., Anderson K. D., Penney J. B. and Young A. B. 1990 Striatal and nigral neuron subpopulations in rigid Huntington’s disease: implications for the functional anatomy of chorea and rigidity-akinesia. Ann. Neurol. 27, 357–365.

    Article  PubMed  CAS  Google Scholar 

  • Albin R. L., Reiner A., Anderson K. D., Dure L. S. 4th, Handelin B., Balfour R. et al. 1992 Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann. Neurol. 31, 425–430.

  • Almqvist E. W., Elterman D. S., MacLeod P. M. and Hayden M. R. 2001 High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Clin. Genet. 60, 198–205.

    Article  PubMed  CAS  Google Scholar 

  • Andrade M. A. and Bork P. 1995 HEAT repeats in the Huntington’s disease protein. Nat. Genet. 11, 115–116.

    Article  PubMed  CAS  Google Scholar 

  • Andrich J., Saft C., Ostholt N. and Müller T. 2007 Complex movement behaviour and progression of Huntington’s disease. Neurosci. Lett.  416, 272–274.

    Article  PubMed  CAS  Google Scholar 

  • Arrasate M., Mitra S., Schweitzer E. S., Segal M. R. and Finkbeiner S. 2004 Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810.

    Article  PubMed  CAS  Google Scholar 

  • Baquet Z. C., Gorski J. A. and Jones K. R. 2004 Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J. Neurosci. 24, 4250–4258.

    Article  PubMed  CAS  Google Scholar 

  • Barker R. A., Mason S. L., Harrower T. P., Swain R. A., Ho A. K., Sahakian B. J. et al. 2013 The long-term safety and efficacy of bilateraltransplantation of human fetal striatal tissue in patients with mild to moderate Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 84, 657–665.

    Article  PubMed  PubMed Central  Google Scholar 

  • Barnes G. T., Duyao M. P., Ambrose C. M., McNeil S., Persichetti F., Srinidhi J. et al. 1994 Mouse Huntington’s disease gene homolog (Hdh). Somat. Cell Mol. Genet. 20, 87–97.

    Article  PubMed  CAS  Google Scholar 

  • Bates E. A., Victor M., Jones A. K., Shi Y. and Hart A. C. 2006 Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity. J. Neurosci. 26, 2830–2838.

    Article  PubMed  CAS  Google Scholar 

  • Baxa M., Hruska-Plochan M., Juhas S., Vodicka P., Pavlok A., Juhasova J. et al. 2013 A transgenic minipig model of Huntington’s disease. J. Huntingtons Dis. 2, 47–68.

    PubMed  CAS  Google Scholar 

  • Baxendale S., Abdulla S., Elgar G., Buck D., Berks M., Micklem G. et al. 1995 Comparative sequence analysis of the human and pufferfish Huntington’s disease genes. Nat. Genet. 10, 67–76.

    Article  PubMed  CAS  Google Scholar 

  • Becher M. W., Kotzuk J. A., Sharp A. H., Davies S. W., Bates G. P., Price D. L. et al. 1998 Intranuclear neuronal inclusions in Huntington’s disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol. Dis. 4, 387–397.

    Article  PubMed  CAS  Google Scholar 

  • Benchoua A., Trioulier Y., Diguet E., Malgorn C., Gaillard M. C., Dufour N. et al. 2008 Dopamine determines the vulnerability of striatal neurons to the N-terminal fragment of mutant huntingtin through the regulation of mitochondrial complex II. Hum. Mol. Genet. 17, 1446–1456.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bender A., Auer D. P., Merl T., Reilmann R., Saemann P., Yassouridis A. et al. 2005 Creatine supplementation lowers brain glutamate levels in Huntington’s disease. J. Neurol. 252, 36–41.

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharyya A., Thakur A. K., Chellgren V. M., Thiagarajan G., Williams A. D., Chellgren B. W. et al. 2006 Oligoproline effects on polyglutamine conformation and aggregation. J. Mol. Biol. 355, 524–535.

    Article  PubMed  CAS  Google Scholar 

  • Bird E. D. and Iversen L. L. 1974 Huntington’s chorea. Post-mortem measurement of glutamic acid decarboxylase, choline acetyltransferase and dopamine in basal ganglia. Brain 97, 457–472.

    Article  PubMed  CAS  Google Scholar 

  • Bird E. D. and Iversen L. L. 1977 Neurochemical findings in Huntington’s chorea. Essays Neurochem. Neuropharmacol. 1, 177–195.

    PubMed  CAS  Google Scholar 

  • Bohnen N. I., Koeppe R. A., Meyer P., Ficaro E., Wernette K., Kilbourn M. R. et al. 2000 Decreased striatal monoaminergic terminals in Huntington disease. Neurology 54, 1753–1759.

    Article  PubMed  CAS  Google Scholar 

  • Branco-Santos J., Herrera F., Poças G. M., Pires-Afonso Y., Giorgini F., Domingos P. M. et al. 2017 Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity. Hum. Mol. Genet. 26, 3763–3775.

    Article  PubMed  CAS  Google Scholar 

  • Brown R. G. and Marsden C. D. 1988 Subcortical dementia’: the neuropsychological evidence. Neuroscience 25, 363–387.

    Article  PubMed  CAS  Google Scholar 

  • Chen Y. Y. and Lai C. H. 2010 Nationwide population-based epidemiologic study of Huntington’s disease in Taiwan. Neuroepidemiology 35, 250–254.

    Article  PubMed  Google Scholar 

  • Chopra V., Fox J. H., Lieberman G., Dorsey K., Matson W., Waldmeier P. et al. 2007 A small-molecule therapeutic lead for Huntington’s disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse. Proc. Natl. Acad. Sci. USA 104, 16685–16689.

    Article  PubMed  Google Scholar 

  • Ciarmiello A., Cannella M., Lastoria S., Simonelli M., Frati L., Rubinsztein D. C. et al. 2006 Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J. Nucl. Med. 47, 215–222.

    PubMed  CAS  Google Scholar 

  • Cicchetti F., Prensa L., Wu Y. and Parent A. 2000 Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington’s disease. Brain Res. Brain Res. Rev. 34, 80–101.

    Article  PubMed  CAS  Google Scholar 

  • Cicchetti F., Lacroix S., Cisbani G., Vallières N., Saint-Pierre M., St-Amour I. et al. 2014 Mutanthuntingtin is present in neuronal grafts in Huntington disease patients. Ann. Neurol. 76, 31–42.

    Article  PubMed  CAS  Google Scholar 

  • Cisbani G. and Cicchetti F. 2014 The fate of cell grafts for the treatment of Huntington’s disease: the post-mortem evidence. Neuropathol. Appl. Neurobiol. 40, 71–90.

    Article  PubMed  CAS  Google Scholar 

  • Como P. G., Rubin A. J., O’Brien C. F., Lawler K., Hickey C., Rubin A. E. et al. 1997 A controlled trial of fluoxetine in nondepressed patients with Huntington’s disease. Mov. Disord. 12, 397–401.

    Article  PubMed  CAS  Google Scholar 

  • Conneally P. M. 1984 Huntington disease: genetics and epidemiology. Am. J. Hum. Genet. 36, 506–526.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Costa V., Giacomello M., Hudec R., Lopreiato R., Ermak G., Lim D. et al. 2010 Mitochondrial fission and cristae disruption increase the response of cell models of Huntington’s disease to apoptotic stimuli. EMBO Mol. Med. 2, 490–503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Davies S. W., Turmaine M., Cozens B. A., DiFiglia M., Sharp A. H., Ross C. A. et al. 1997 Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548.

    Article  PubMed  CAS  Google Scholar 

  • de Yebenes J. G., Landwehrmeyer B., Squitieri F., Reilmann R., Rosser A., Barker R. A. et al. 2011 Pridopidine for the treatment of motor function in patients with Huntington’sdisease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlledtrial. Lancet Neurol. 10, 1049–1057.

    Article  PubMed  CAS  Google Scholar 

  • del Toro D., Alberch J., Lázaro-Diéguez F., Martín-Ibáñez R., Xifró X., Egea G. et al. 2009 Mutant huntingtin impairs post-Golgi trafficking to lysosomes bydelocalizing optineurin/Rab8 complex from the Golgi apparatus. Mol. Biol. Cell. 20, 1478–1492.

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Maio L., Squitieri F., Napolitano G., Campanella G. and Trofatter J. A. 1993 Conneally suicide risk in Huntington’s disease J. Med. Genet. 30, 293–295.

    Article  PubMed  PubMed Central  Google Scholar 

  • DiFiglia M. 1990 Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends Neurosci. 13, 286–289.

    Article  PubMed  CAS  Google Scholar 

  • DiGiovanni L. F., Mocle A. J., Xia J. and Truant R. 2016 Huntingtin N17 domain is a reactiveoxygen species sensor regulating huntingtin phosphorylation and localization. Hum. Mol. Genet. 25, 3937–3945.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dom R., Malfroid M. and Baro F. 1976. Neuropathology of Huntington’s chorea. Studies of the ventrobasal complex of the thalamus. Neurology 26, 64–68.

    Article  PubMed  CAS  Google Scholar 

  • El-Daher M. T., Hangen E., Bruyère J., Poizat G., Al-Ramahi I., Pardo R. et al. 2015 Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation. EMBO J. 34, 2255–2271.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Emerich D. F., Norman A. B. and Sanberg P. R. 1991 Nicotine potentiates the behavioral effects of haloperidol. Psychopharmacol. Bull. 27, 385–390.

    PubMed  CAS  Google Scholar 

  • Enna S. J., Bird E. D., Bennett Jr J. P., Bylund D. B., Yamamura H. I., Iversen L. L. et al. 1976 Huntington’s chorea. Changes in neurotransmitter receptors in the brain. N. Engl. J. Med. 294, 1305–1309.

    Article  PubMed  CAS  Google Scholar 

  • Evans S. J., Douglas I., Rawlins M. D., Wexler N. S., Tabrizi S. J. and Smeeth L. 2013 Prevalence of adult Huntington’s disease in the UK based on diagnoses recorded in general practice records. J. Neurol. Neurosurg. Psychiatry 84, 1156–1160.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ferrante R. J., Kowall N. W., Beal M. F., Martin J. B., Bird E. D. and Richardson Jr E. P. 1987 Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington’s disease. J. Neuropathol. Exp. Neurol. 46, 12–27.

    Article  PubMed  CAS  Google Scholar 

  • Ferrer I., Goutan E., Marín C., Rey M. J. and Ribalta T. 2000 Brain-derived neurotrophic factor in Huntington disease. Brain Res. 866, 257–261.

    Article  PubMed  CAS  Google Scholar 

  • Finkbeiner S. 2011 Huntington’s disease. Cold Spring Harbor Laboratory Press, Cold Spring Harbor.

  • Fisher E. R. and Hayden M. R. 2014 Multisource ascertainment of Huntington disease in Canada: prevalence and population at risk. Mov. Disord. 29, 105–114.

    Article  PubMed  Google Scholar 

  • Folstein S. E., Chase G. A., Wahl W. E., McDonnell A. M. and Folstein M. F. 1987 Huntington disease in Maryland: clinical aspects of racial variation. Am. J. Hum. Genet. 41, 168–179.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Futter M., Diekmann H., Schoenmakers E., Sadiq O., Chatterjee K. and Rubinsztein D. C. 2009 Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors. J. Med. Genet. 46, 438–446.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gasset-Rosa F., Chillon-Marinas C., Goginashvili A., Atwal R. S., Artates J. W., Tabet R et al. 2017 Polyglutamine-expanded Huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron 94, 48–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gauthier L. R., Charrin B. C., Borrell-Pagès M., Dompierre J. P., Rangone H., Cordelières F. P. et al. 2004 Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127–138.

    Article  PubMed  CAS  Google Scholar 

  • Gerfen C. R. 1992 The neostriatal mosaic: multiple levels of compartmental organization. J. Neural. Transm. Suppl. 36, 43–59.

    PubMed  CAS  Google Scholar 

  • Girotti F., Carella F., Scigliano G., Grassi M. P., Soliveri P., Giovannini P. et al. 1984 Effect of neuroleptic treatment on involuntary movements and motor performances in Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 47, 848–852.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Graham R. K., Slow E. J., Deng Y., Bissada N., Lu G., Pearson J. et al. 2005 Levels of mutant huntingtin influence the phenotypic severity of Huntington disease in YAC128 mouse models. Neurobiol. Dis. 21, 444–455.

    Article  PubMed  CAS  Google Scholar 

  • Graybiel A. M., Ohta K. and Roffler-Tarlov S. 1990 Patterns of cell and fiber vulnerability in the mesostriatal system of the mutant mouse weaver. I. Gradients and compartments. J. Neurosci. 10, 720–733.

    PubMed  CAS  Google Scholar 

  • Grima J. C., Daigle J. G., Arbez N., Cunningham K. C., Zhang K., Ochaba J. et al. 2017 Mutant Huntingtin disrupts the nuclear pore complex. Neuron 94, 93–107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grote H. E., Bull N. D., Howard M. L., van Dellen A., Blakemore C., Bartlett P. F. et al. 2005 Cognitive disorders and neurogenesis deficits in Huntington’s disease mice are rescued by fluoxetine. Eur. J. Neurosci. 22, 2081–2088.

    Article  PubMed  Google Scholar 

  • Gu X., Cantle J. P., Greiner E. R., Lee C. Y., Barth A. M., Gao F. et al. 2015 N17 Modifies mutant Huntingtin nuclear pathogenesis and severity of disease in HD BAC transgenic mice. Neuron 85, 726–741.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gunawardena S., Her L. S., Brusch R. G., Laymon R. A., Niesman I. R., Gordesky-Gold B. et al. 2003 Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40, 25–40.

    Article  PubMed  CAS  Google Scholar 

  • Gutekunst C. A., Li S. H., Yi H., Mulroy J. S., Kuemmerle S., Jones R. et al. 1999 Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J. Neurosci. 19, 2522–2534.

    Article  PubMed  CAS  Google Scholar 

  • Haremaki T., Deglincerti A. and Brivanlou A. H. 2015 Huntingtin is required forciliogenesis and neurogenesis during early Xenopus development. Dev. Biol. 408, 305–315.

    Article  PubMed  CAS  Google Scholar 

  • Harper P. S. 2002 Huntington’s disease: a historical background in Huntington’s disease (ed. G. Bates, P. S. Harper and L. Jones), pp. 3–37. Oxford University Press, Oxford.

  • Harper P. S., Walker D. A., Tyler A., Newcombe R. G. and Davies K. 1979 Huntington’s chorea. The basis for long-term prevention. Lancet 2, 346–349.

    PubMed  CAS  Google Scholar 

  • Hartl F. U. 2016 Cellular homeostasis and aging. Ann. Rev. Biochem. 85, 1–4.

    Article  PubMed  CAS  Google Scholar 

  • Hedreen J. C. and Folstein S. E. 1995 Early loss of neostriatal striosome neurons in Huntington’s disease. J. Neuropathol. Exp. Neurol. 54, 1051–1020.

    Article  Google Scholar 

  • Hedreen J. C., Peyser C. E., Folstein S. E. and Ross C. A. 1991 Neuronal loss in layers V and VI of cerebral cortex in Huntington’s disease. Neurosci. Lett. 133, 257–261.

    Article  PubMed  CAS  Google Scholar 

  • Heinsen H., Strik M., Bauer M., Luther K., Ulmar G., Gangnus D. et al. 1994 Cortical and striatal neurone number in Huntington’s disease Acta. Neuropathol. 88, 320–333.

    Article  CAS  Google Scholar 

  • Heinsen H., Rüb U., Gangnus D., Jungkunz G., Bauer M., Ulmar G. et al. 1996 Nerve cell loss in the thalamic centromedian-parafascicular complex in patients with Huntington’s disease. Acta. Neuropathol. 91, 161–168.

    Article  PubMed  CAS  Google Scholar 

  • Hodges A., Strand A. D., Aragaki A. K., Kuhn A., Sengstag T., Hughes G. et al. 2006 Regional and cellular gene expression changes in human Huntington’s disease brain. Hum. Mol. Genet. 15, 965–977.

    Article  PubMed  Google Scholar 

  • Hodgson J. G., Agopyan N., Gutekunst C. A., Leavitt B. R., LePiane F., Singaraja R. et al. 1999 A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23, 181–192.

    Article  PubMed  CAS  Google Scholar 

  • Huang K., Sanders S. S., Kang R., Carroll J. B., Sutton L., Wan J. et al. 2011 Wild-type HTT modulates the enzymatic activity of the neuronal palmitoyl transferase HIP14. Hum. Mol. Genet. 20, 3356–3365.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Huntington G. 1872 On chorea. Med. Surg. Rep. 26, 317–321.

    Google Scholar 

  • Huntington Study Group 2001 A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 14, 397–404.

  • Huntington Study Group 2006 Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 66, 366 –372.

  • Huntington Study Group HART Investigators 2013 A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov. Disord. 28, 1407–1415.

  • Jacobsen J. C., Bawden C. S., Rudiger S. R., McLaughlan C. J., Reid S. J., Waldvogel H. J. et al. 2010 An ovine transgenic Huntington’s disease model. Hum. Mol. Genet. 19, 1873–1882.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jeste D. V., Barban L. and Parisi J. 1984 Reduced Purkinje cell density in Huntington’s disease. Exp. Neurol. 85, 78–86.

    Article  PubMed  CAS  Google Scholar 

  • Kakkar V., Meister-Broekema M., Minoia M., Carra S. and Kampinga H. H. 2014 Barcoding heat shock proteins to human diseases: looking beyond the heat shock response. Dis. Model Mech. 7, 421–434.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kamat P. K., Kalani A., Kyles P., Tyagi S. C. and Tyagi N. 2014 Autophagy of mitochondria: a promising therapeutic target for neurodegenerative disease. Cell Biochem. Biophys. 70, 707–719.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Karlovich C. A., John R. M., Ramirez L., Stainier D. Y. and Myers R. M. 1998 Characterization of the Huntington’s disease (HD) gene homologue in the zebrafish Danio rerio. Gene 217, 117–121.

    Article  PubMed  CAS  Google Scholar 

  • Kenney C., Hunter C. and Jankovic J. 2007 Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov. Disord. 15, 193–197.

    Article  Google Scholar 

  • Keryer G., Pineda J. R., Liot G., Kim J., Dietrich P., Benstaali C. et al. 2011 Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J. Clin. Invest. 121, 4372–4382.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim Y. E., Hosp F., Frottin F., Ge H., Mann M., Hayer-Hartl M. et al. 2016 Soluble oligomers of PolyQ-expanded Huntingtin target a multiplicity of key cellular factors. Mol. Cell 63, 951–964.

    Article  PubMed  CAS  Google Scholar 

  • Kingma E. M., van Duijn E., Timman R., van der Mast R. C. and Roos R. A. 2008 Behavioural problems in Huntington’s disease using the problem behaviours assessment. Gen. Hosp. Psychiatry. 30, 155–161.

    Article  PubMed  Google Scholar 

  • Kirkwood S. C., Siemers E., Viken R., Hodes M. E., Conneally P. M., Christian J. C. et al. 2002 Longitudinal personality changes among presymptomatic Huntington disease gene carriers. Neuropsychiatry Neuropsychol. Behav. Neurol. 15, 192–197.

    PubMed  Google Scholar 

  • Kish S. J., Shannak K. and Hornykiewicz O. 1987 Elevated serotonin and reduced dopamine in subregionally divided Huntington’s disease striatum. Ann. Neurol. 22, 386–389.

    Article  PubMed  CAS  Google Scholar 

  • Kokmen E., Ozekmekci F. S., Beard C. M., O’Brien P. C. and Kurland L. T. 1994 Incidence and prevalence of Huntington’s disease in Olmsted County, Minnesota (1950 through 1989). Arch. Neurol. 51, 696–698.

    Article  PubMed  CAS  Google Scholar 

  • Koller W. C. and Trimble J. 1985 Gait abnormality of Huntington’s disease. Neurology 35, 1450–1454.

    Article  PubMed  CAS  Google Scholar 

  • Koyuncu S., Fatima A., Gutierrez-Garcia R. and Vilchez D. 2017 Proteostasis of huntingtin in health and disease. Int. J. Mol. Sci. 19, 18.

    Article  Google Scholar 

  • Krench M. and Littleton J. T. 2013 Modeling Huntington disease in Drosophila: Insights into axonal transport defects and modifiers of toxicity. Fly (Austin) 7, 229–236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Krobitsch S. and Lindquist S. 2000 Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins. Proc. Natl. Acad. Sci. USA 97, 1589–1594.

    Article  PubMed  CAS  Google Scholar 

  • Labadorf A., Hoss A. G., Lagomarsino V, Latourelle J. C., Hadzi T. C., Bregu J. 2015 RNA Sequence analysis of human Huntington disease brain reveals an extensive increase in inflammatory and developmental gene expression. PLoS One 10, e0143563.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Legendre-Guillemin V., Metzler M., Charbonneau M., Gan L., Chopra V., Philie J. et al. 2002 HIP1 and HIP12 display differential binding to F-actin, AP2, and clathrin. Identification of a novel interaction with clathrin lightchain. J. Biol. Chem. 277, 19897–19904.

    Article  PubMed  CAS  Google Scholar 

  • Leonard D. P., Kidson M. A., Brown J. G., Shannon P. J. and Taryan S. 1975 A double blind trial of Lithium carbonate and haloperidol in Huntington’s chorea. Aust. N Z J. 9, 115–118.

    Article  CAS  Google Scholar 

  • Li X., Sapp E., Valencia A., Kegel K. B., Qin Z. H., Alexander J. et al. 2008 A function of huntingtin in guanine nucleotide exchange on Rab11. Neuroreport 19, 1643–1647.

    Article  PubMed  CAS  Google Scholar 

  • Lin B., Rommens J. M., Graham R. K., Kalchman M., MacDonald H., Nasir J. et al. 1993 Differential 3’ polyadenylation of the Huntington disease gene results in two mRNA species with variable tissue expression. Hum. Mol. Genet. 2, 1541–1545.

    Article  PubMed  CAS  Google Scholar 

  • Lin L., Park J. W., Ramachandran S., Zhang Y., Tseng Y. T., Shen S. et al. 2016 Transcriptome sequencing reveals aberrant alternative splicing in Huntington’s disease. Hum. Mol. Genet. 25, 3454–3466.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liot G., Zala D., Pla P., Mottet G., Piel M. and Saudou F. 2013 Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J. Neurosci. 33, 6298–6309.

    Article  PubMed  CAS  Google Scholar 

  • Lloyd K. G., Dreksler S. and Bird E. D. 1977 Alterations in 3H-GABA binding in Huntington’s chorea. Life Sci. 21, 747–753.

    Article  PubMed  CAS  Google Scholar 

  • Lundin A., Dietrichs E., Haghighi S., Göller M. L., Heiberg A., Loutfi G. et al. 2010 Efficacy and safety of the dopaminergic stabilizer Pridopidine (ACR16) inpatients with Huntington’s disease. Clin. Neuropharmacol. 33, 260–264.

    Article  PubMed  CAS  Google Scholar 

  • Macdonald V., Halliday G. M., Trent R. J. and McCusker E. A. 1997 Significant loss of pyramidal neurons in the angular gyrus of patients with Huntington’s disease. Neuropathol. Appl. Neurobiol. 23, 492–495.

    Article  PubMed  CAS  Google Scholar 

  • Mangiarini L., Sathasivam K., Seller M., Cozens B., Harper A., Hetherington C. et al. 1996 Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice Cell 87, 493–506.

    Article  PubMed  CAS  Google Scholar 

  • Marques Sousa C. and Humbert S. 2013 Huntingtin: here, there, everywhere! J. Huntingtons Dis. 2, 395–403.

    PubMed  Google Scholar 

  • Marsden C. D. 1973 Drug treatment of diseases characterized by abnormal movements. Proc. R. Soc. Med. 66, 871–873.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Martin D. D., Ladha S., Ehrnhoefer D. E. and Hayden M. R. 2015 Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci. 38, 26–35.

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S. et al. 2010 Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat. Neurosci. 13, 567–576.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Matthews R. T., Yang L., Browne S., Baik M. and Beal M. F. 1998 Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc. Natl. Acad. Sci. USA 95, 8892–8897.

    Article  PubMed  CAS  Google Scholar 

  • McCaughey W. T. E. 1961 The pathologic spectrum of Huntington’s Chorea. J. Nerv. Ment. Dis. 133, 91–103.

    Article  Google Scholar 

  • McCusker E. A., Casse R. F., Graham S. J., Williams D. B. and Lazarus R. 2000 Prevalence of Huntington disease in New South Wales in 1996. Med. J. Aust. 173, 187–190.

    PubMed  CAS  Google Scholar 

  • Miller J., Arrasate M., Shaby B. A., Mitra S., Masliah E. and Finkbeiner S. 2010 Quantitative relationships between huntingtin levels, polyglutamine length, inclusion body formation, and neuronal death provide novel insight into Huntington’s disease molecular pathogenesis. J. Neurosci. 30, 10541–10550.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Miller J. R., Lo K. K., Andre R., Hensman Moss D. J., Träger U., Stone T. C. et al. 2016 RNA-Seq of Huntington’s disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation. Hum. Mol. Genet. 25, 2893–2904.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Morrison P. J., Johnston W. P. and Nevin N. C. 1995 The epidemiology of Huntington’s disease in Northern Ireland. J. Med. Genet. 32, 524–530.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Myers R. H., Vonsattel J. P., Stevens T. J., Cupples L. A., Richardson E. P., Martin J. B. et al. 1988 Clinical and neuropathologic assessment of severity in Huntington’s disease. Neurology 38, 341–347.

    Article  PubMed  CAS  Google Scholar 

  • Narain Y., Wyttenbach A., Rankin J., Furlong R. A. and Rubinsztein D. C. 1999 A molecular investigation of true dominance in Huntington’s disease. J. Med. Genet. 36, 739–746.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Neuwald A. F. and Hirano T. 2000 HEAT repeats associated with condensins, cohesins, and other complexes involved in chromosome-related functions. Genome Res. 10, 1445–1452.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nguyen K. Q., Rymar V. V. and Sadikot A. F. 2016 Impaired TrkB Signaling Underlies reduced BDNF-mediated trophic support of striatal neurons in the R6/2 mouse model of Huntington’s disease. Front Cell Neurosci. 9, 37.

    Article  Google Scholar 

  • Nørremølle A., Riess O., Epplen J. T., Fenger K., Hasholt L. and Sørensen S. A. 1993 Trinucleotide repeat elongation in the Huntingtin gene in Huntington disease patients from 71 Danish families. Hum. Mol. Genet. 2, 1475–1476.

    Article  PubMed  Google Scholar 

  • Novak M. J. and Tabrizi S. J. 2010 Huntington’s disease. BMJ 30, 340.

    Google Scholar 

  • Okun M. S. and Thommi N. 2004 Americo Negrette (1924 to 2003): diagnosing Huntington disease in Venezuela. Neurology 63, 340–343.

    Article  PubMed  Google Scholar 

  • Paganini M., Biggeri A., Romoli A. M., Mechi C., Ghelli E., Berti V. et al. 2014 Fetal striatal grafting slows motor and cognitive decline of Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 85, 974–981.

    Article  PubMed  Google Scholar 

  • Palo J., Somer H., Ikonen E., Karila L. and Peltonen L. 1987 Low prevalence of Huntington’s disease in Finland. Lancet 2, 805–806.

    Article  PubMed  CAS  Google Scholar 

  • Pandey M., Mohanakumar K. P. and Usha R. 2010 Mitochondrial functional alterations in relation to pathophysiology of Huntington’s disease. J. Bioenerg. Biomembr. 42, 217–226.

    Article  PubMed  CAS  Google Scholar 

  • Paul B. D., Sbodio J. I., Xu R., Vandiver M. S., Cha J. Y., Snowman A. M. et al. 2014 Cystathionine \(\upgamma \)-lyase deficiency mediates neurodegeneration in Huntington’s disease. Nature 509, 96–100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pavese N., Andrews T. C., Brooks D. J., Ho A. K., Rosser A. E., Barker R. A. et al. 2003 Progressive striatal and cortical dopamine receptor dysfunction in Huntington’s disease: a PET study. Brain 126, 1127–1135.

    Article  PubMed  Google Scholar 

  • Perry T. L., Hansen S. and Kloster M. 1973 Huntington’s chorea. Deficiency of gamma-aminobutyric acid in brain. N. Engl. J. Med. 288, 337–342.

    Article  PubMed  CAS  Google Scholar 

  • Peterlin B., Kobal J., Teran N., Flisar D. and Lovrecić L. 2009 Epidemiology of Huntington’s disease in Slovenia. Acta. Neurol. Scand. 119, 371–375.

    Article  PubMed  CAS  Google Scholar 

  • Pleydell M. J. 1955 Huntington’s chorea in Northamptonshire. Br. Med. J. 2, 889.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Precious S. V., Zietlow R, Dunnett S. B., Kelly C. M. and Rosser A. E. 2017 Is there a place for human fetal–derived stem cells for cell replacement therapy in Huntington’s disease? Neurochem. Int. 106, 114–121.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pridmore S. A. 1990 The prevalence of Huntington’s disease in Tasmania. Med. J. Aust. 153, 133–134.

    PubMed  CAS  Google Scholar 

  • Ramdzan Y. M., Trubetskov M. M., Ormsby A. R., Newcombe E. A., Sui X., Tobin M. J. et al. 2017 Huntingtin inclusions trigger cellular quiescence, deactivate apoptosis, and lead to delayed necrosis. Cell Rep. 19, 919–927.

    Article  PubMed  CAS  Google Scholar 

  • Ravikumar B., Vacher C., Berger Z., Davies J. E., Luo S., Oroz L. G. et al. 2004 Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595.

    Article  PubMed  CAS  Google Scholar 

  • Reddy P. H., Williams M., Charles V., Garrett L., Pike-Buchanan L., Whetsell W. O. Jr et al. 1998 Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full–length HD cDNA. Nat. Genet. 20, 198–202.

    Article  PubMed  CAS  Google Scholar 

  • Reed T. E. and Chandler J. H. 1958 Huntington’s chorea in Michigan. I. Demography and genetics. Am. J. Hum. Genet. 10, 201–225.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Reilmann R. 2013 The pridopidine paradox in Huntington’s disease. Mov. Disord. 28, 1321–1324.

    Article  PubMed  CAS  Google Scholar 

  • Reiner A., Albin R. L., Anderson K. D., D’Amato C. J., Penney J. B. and Young A. B. 1988 Differential loss of striatal projection neurons in Huntington disease. Proc. Natl. Acad. Sci. USA 85, 5733–5737.

    Article  PubMed  CAS  Google Scholar 

  • Reynolds G. P. and Garrett N. J. 1986 Striatal dopamine and homovanillic acid in Huntington’s disease. J. Neural. Transm. 65, 151–155.

    Article  PubMed  CAS  Google Scholar 

  • Reynolds G. P. and Pearson S. J. 1987 Decreased glutamic acid and increased 5-hydroxytryptamine in Huntington’s disease brain. Neurosci. Lett. 78, 233–238.

    Article  PubMed  CAS  Google Scholar 

  • Ribaï P., Nguyen K., Hahn-Barma V., Gourfinkel-An I., Vidailhet M., Legout A. et al. 2007 Psychiatric and cognitive difficulties as indicators of juvenile Huntington disease onset in 29 patients. Arch. Neurol. 64, 813–819.

    Article  PubMed  Google Scholar 

  • Rodda R. A. 1981 Cerebellar atrophy in Huntington’s disease. J. Neurol. Sci. 50, 147–157.

    Article  PubMed  CAS  Google Scholar 

  • Rosas H. D., Salat D. H., Lee S. Y., Zaleta A. K., Pappu V., Fischl B. et al. 2008 Cerebral cortex and the clinical expression of Huntington’s disease: complexity and heterogeneity. Brain 131, 1057–1068.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ross C. A. and Tabrizi S. J. 2011 Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 10, 83–98.

    Article  PubMed  CAS  Google Scholar 

  • Rubinsztein D. C., Leggo J., Coles R., Almqvist E., Biancalana V., Cassiman J. J. et al. 1996 Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am. J. Hum. Genet. 59, 16–22.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Sapp E., Kegel K. B., Aronin N., Hashikawa T., Uchiyama Y., Tohyama K. et al. 2001 Early and progressive accumulation of reactive microglia in the Huntington disease brain. J. Neuropathol. Exp. Neurol. 60, 161–172.

    Article  PubMed  CAS  Google Scholar 

  • Saudou F. and Humbert S. 2016 The biology of Huntingtin. Neuron 89, 910–926.

    Article  PubMed  CAS  Google Scholar 

  • Schmitt I., Bächner D., Megow D., Henklein P., Hameister H., Epplen J. T. et al. 1995 Expression of the Huntington disease gene in rodents: cloning the rat homologue and evidence for downregulation in non-neuronal tissues during development. Hum. Mol. Genet. 4, 1173–1182.

    Article  PubMed  CAS  Google Scholar 

  • Schoenfeld M., Myers R. H., Cupples L. A., Berkman B., Sax D. S. and Clark E. 1984 Increased rate of suicide among patients with Huntington’s disease. J. Neurol. Neurosurg. Psychiatry 47, 1283–1287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Seto-Ohshima A., Emson P. C., Lawson E., Mountjoy C. Q. and Carrasco L. H. 1988 Loss of matrix calcium-binding protein-containing neurons in Huntington’s disease. Lancet 1, 1252–1255.

    Article  PubMed  CAS  Google Scholar 

  • Shiwach R. S. and Lindenbaum R. H. 1990 Prevalence of Huntington’s disease among UK immigrants from the Indian subcontinent. Br. J. Psychiatry 157, 598–599.

    Article  PubMed  CAS  Google Scholar 

  • Shokeir M. H. 1975 Investigations on Huntington’s disease in the Canadian Prairies. I. Prevalence. Clin. Genet. 7, 345–348.

    Article  PubMed  CAS  Google Scholar 

  • Shoulson I., Goldblatt D., Charlton M. and Joynt R. J. 1978 Huntington’s disease: treatment with muscimol, a GABA-mimetic drug. Ann. Neurol. 4, 279–284.

    Article  PubMed  CAS  Google Scholar 

  • Simpson S. A. and Johnston A. W. 1989 The prevalence and patterns of care of Huntington’s chorea in Grampian. Br. J. Psychiatry 155, 799–804.

    Article  PubMed  CAS  Google Scholar 

  • Slow E. J., Graham R. K., Osmand A. P., Devon R. S., Lu G., Deng Y. et al. 2005 Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc. Natl. Acad. Sci. USA 102, 11402–11407.

    Article  PubMed  CAS  Google Scholar 

  • Smith R., Chung H., Rundquist S., Maat-Schieman M. L., Colgan L., Englund E. et al. 2006 Cholinergic neuronal defect without cell loss in Huntington’s disease. Hum. Mol. Genet. 15, 3119–3131.

    Article  PubMed  CAS  Google Scholar 

  • Song W., Chen J., Petrilli A., Liot G., Klinglmayr E., Zhou Y. et al. 2011 Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat. Med. 17, 377–382.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Spargo E., Everall I. P. and Lantos P. L. 1993 Neuronal loss in the hippocampus in Huntington’s disease: a comparison with HIV infection. J. Neurol. Neurosurg. Psychiatry. 56, 487–491.

    Article  CAS  Google Scholar 

  • Spires T. L. and Hannan A. J. 2007 Molecular mechanisms mediating pathological plasticity in Huntington’s disease and Alzheimer’s disease. J. Neurochem. 100, 874–882.

    Article  PubMed  CAS  Google Scholar 

  • Spokes E. G. 1980 Neurochemical alterations in Huntington’s chorea: a study of post–mortem brain tissue. Brain 103, 179–210.

    Article  PubMed  CAS  Google Scholar 

  • Steffan J. S., Kazantsev A., Spasic-Boskovic O., Greenwald M., Zhu Y. Z., Gohler H. et al. 2000 The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. USA 97, 6763–6768.

    Article  PubMed  CAS  Google Scholar 

  • Steffan J. S., Agrawal N., Pallos J., Rockabrand E., Trotman L. C., Slepko N. et al. 2004 SUMO modification of Huntingtin and Huntington’s disease pathology. Science 304, 100–104.

    Article  PubMed  CAS  Google Scholar 

  • Steffan J. S. 2010 Does Huntingtin play a role in selective macroautophagy? Cell Cycle 9, 3401–341.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Suhr S. T., Senut M. C., Whitelegge J. P., Faull K. F., Cuizon D. B. and Gage F. H. 2001 Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. J. Cell Biol. 153, 283–294.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tabrizi S. J., Scahill R. I., Owen G., Durr A., Leavitt B. R., Roos R. A. et al. 2013 Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol. 12, 637–649.

    Article  PubMed  Google Scholar 

  • Tagawa K., Marubuchi S., Qi M. L., Enokido Y., Tamura T., Inagaki R. et al. 2007 The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes. J. Neurosci. 27, 868–880.

    Article  PubMed  CAS  Google Scholar 

  • Takano H. and Gusella J. F. 2002 The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci. 3, 15.

    Article  PubMed  PubMed Central  Google Scholar 

  • Thakur A. K., Jayaraman M., Mishra R., Thakur M., Chellgren V. M., Byeon I. J. et al. 2009 Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism. Nat. Struct. Mol. Biol. 16, 380–389.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • The Huntington’s Disease Collaborative Research Group 1993 A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983.

  • Trushina E., Dyer R. B., Badger J. D. 2nd, Ure D., Eide L., Tran D. D. et al. 2004 Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol. Cell Biol. 24, 8195–8209.

  • Turjanski N., Weeks R., Dolan R., Harding A. E. and Brooks D. J. 1995 Striatal \(\text{ D }_{1}\) and \(\text{ D }_{2}\) receptor binding in patients with Huntington’s disease and other choreas. A PET study. Brain 118, 689–696.

    PubMed  Google Scholar 

  • Twelvetrees A. E., Yuen E. Y., Arancibia-Carcamo I. L., MacAskill A. F., Rostaing P., Lumb M. J. et al. 2010 Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron 65, 53–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Valor L. M. 2015 Transcription, epigenetics and ameliorative strategies in Huntington’s Disease: a genome–wide perspective. Mol. Neurobiol. 51, 406–423.

    Article  PubMed  CAS  Google Scholar 

  • van Hagen M., Piebes D. G. E., de Leeuw W. C., Vuist I. M., van Roon-Mom W. M. C., Moerland P. D. et al. 2017 The dynamics of early-state transcriptional changes and aggregate formation in a Huntington’s disease cell model. BMC Genomics 18, 373.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Veldman M. B., Rios-Galdamez Y., Lu X. H., Gu X., Qin W., Li S. et al. 2015 The N17 domain mitigates nuclear toxicity in a novel zebrafish Huntington’s disease model. Mol. Neurodegener. 10, 67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Verbessem P., Lemiere J., Eijnde B. O., Swinnen S., Vanhees L., Van Leemputte M. et al. 2003 Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology 61, 925–930.

    Article  PubMed  CAS  Google Scholar 

  • Verny C., Allain P., Prudean A., Malinge M. C., Gohier B., Scherer C. et al. 2007 Cognitive changes in asymptomatic carriers of the Huntington disease mutation gene. Eur. J. Neurol. 14, 1344–1350.

    Article  PubMed  CAS  Google Scholar 

  • Videnovic A., Leurgans S., Fan W., Jaglin J. and Shannon K. M. 2009 Daytime somnolence and nocturnal sleep disturbances in Huntington disease. Parkinsonism Relat. Disord. 15, 471–474

    Article  PubMed  Google Scholar 

  • Vonsattel J. P. and DiFiglia M. 1998 Huntington disease. J. Neuropathol. Exp. Neurol. 57, 369–384.

    CAS  Google Scholar 

  • Vonsattel J. P., Myers R. H., Stevens T. J., Ferrante R. J., Bird E. D. and Richardson E. P. Jr. 1985 Neuropathological classification of Huntington’s disease. J. Neuropathol. Exp. Neurol. 44, 559–577.

    Article  CAS  Google Scholar 

  • Walker F. O. 2007 Huntington’s disease. Lancet 369, 218–228.

    Article  PubMed  CAS  Google Scholar 

  • Wexler N. S., Lorimer J., Porter J., Gomez F., Moskowitz C., Shackell E. et al. 2004 Venezuelan kind reds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc. Natl. Acad. Sci. USA 101, 3498–3503.

    Article  PubMed  CAS  Google Scholar 

  • Wolf R. C., Vasic N., Schönfeldt-Lecuona C., Ecker D. and Landwehrmeyer G. B. 2009 Cortical dysfunction in patients with Huntington’s disease during working memory performance. Hum. Brain Mapp. 30, 327–329.

    Article  PubMed  Google Scholar 

  • Wong Y. C. and Holzbaur E. L. 2014 The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J. Neurosci. 34, 1293–1305.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wright H. H., Still C. N. and Abramson R. K. 1981 Huntington’s disease in black kindreds in South Carolina. Arch. Neurol. 38, 412–414.

    Article  PubMed  CAS  Google Scholar 

  • Xi W., Wang X., Laue T. M. and Denis C. L. 2016 Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington’s disease model system. Sci. Rep. 6, 34916.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yanai A., Huang K., Kang R., Singaraja R. R., Arstikaitis P., Gan L. et al. 2006 Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat. Neurosci. 9, 824–831.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yang S. H., Cheng P. H., Banta H., Piotrowska-Nitsche K., Yang J. J., Cheng E. C. et al. 2008 Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 453, 921–924.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zakzanis K. K. 1998 The subcortical dementia of Huntington’s disease. J. Clin. Exp. Neuropsychol. 20, 565–578.

    Article  PubMed  CAS  Google Scholar 

  • Zala D., Hinckelmann M. V. and Saudou F. 2013 Huntingtin’s function in axonal transport is conserved in Drosophila melanogaster. PLoS One 8, 3.

    Article  CAS  Google Scholar 

  • Zeitlin S., Liu J. P., Chapman D. L., Papaioannou V. E. and Efstratiadis A. 1995 Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat. Genet. 11, 155–163.

    Article  PubMed  CAS  Google Scholar 

  • Zuchner T. and Brundin P. 2008 Mutant huntingtin can paradoxically protect neurons from death. Cell Death Differ. 15, 435–442.

    Article  PubMed  CAS  Google Scholar 

  • Zühlke C., Riess O., Bockel B., Lange H. and Thies U. 1993 Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene. Hum. Mol. Genet. 2, 2063–2067.

Download references

Author information

Authors and Affiliations

  1. Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD,  20892, USA

    Mritunjay Pandey

  2. Inter University Center for Biomedical Research and Super Specialty Hospital, Kottayam, 686 009, India

    Usha Rajamma

Authors
  1. Mritunjay Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Usha Rajamma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Usha Rajamma.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pandey, M., Rajamma, U. Huntington’s disease: the coming of age. J Genet 97, 649–664 (2018). https://doi.org/10.1007/s12041-018-0957-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12041-018-0957-1

Keywords

Search

Navigation