Skip to main content
SpringerLink
Log in

Huntington’s disease: A decade beyond gene discovery

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Huntington’s disease is a dominantly inherited neurodegenerative disease that causes a progressive movement disorder, cognitive decline, and varying degrees of psychiatric dysfunction. The identification of the mutant gene in 1993 paved the way for a decade of basic research. The resultant advances in our understanding of the pathogenesis of the disorder are moving us toward rational therapies to slow the progression and delay the onset of the illness.

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

Similar content being viewed by others

References and Recommended Reading

  1. Huntington G: On chorea. The Medical & Surgical Reporter 1872, 26:320–321.

    Google Scholar 

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

    Article  Google Scholar 

  3. Schoenfeld M, Myers RH, Cupples LA, et al.: Increased rate of suicide among patients with Huntington’s disease. J Neurol Neurosurg Psychiatry 1984, 47:1283–1287.

    Article  PubMed  CAS  Google Scholar 

  4. Folstein SE, Chase GA, Wahl WE, et al.: Huntington disease in Maryland: clinical aspects of racial variation. Am J Hum Genet 1987, 41:168–179.

    PubMed  CAS  Google Scholar 

  5. Lipe H, Schultz A, Bird TD: Risk factors for suicide in Huntington’s disease: a retrospective case controlled study. Am J Med Genet 1993, 48:231–233.

    Article  PubMed  CAS  Google Scholar 

  6. Rosenblatt A, Leroi I: Neuropsychiatry of Huntington’s disease and other basal ganglia disorders. Psychosomatics 2000, 41:24–30.

    PubMed  CAS  Google Scholar 

  7. Rubinsztein DC, Leggo J, Coles R, et al.: 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 1996, 59:16–22.

    PubMed  CAS  Google Scholar 

  8. Almquist E, Elterman D, MacLeod P, Hayden M: High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Clin Neurogenet 2001, 60:198–205.

    Article  Google Scholar 

  9. Rubinsztein DC, Amos W, Leggo J, et al.: Mutational bias provides a model for the evolution of Huntington’s disease and predicts a general increase in disease prevalence. Nat Genet 1994, 7:525–530.

    Article  PubMed  CAS  Google Scholar 

  10. Panas M, Avramopoulos D, Karadima G, et al.: Apolipoprotein E and presenilin-1 genotypes in Huntington’s disease. J Neurol 1999, 246:574–577.

    Article  PubMed  CAS  Google Scholar 

  11. Kehoe P, Krawczak M, Harper PS, et al.: Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J Med Genet 1999, 36:108–111.

    PubMed  CAS  Google Scholar 

  12. Rubinsztein DC, Leggo J, Chiano M, et al.: Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci U S A 1997, 94:3872–3876.

    Article  PubMed  CAS  Google Scholar 

  13. MacDonald ME, Vonsattel JP, Shrinidhi J, et al.: Evidence for the GluR6 gene associated with younger onset age of Huntington’s disease. Neurology 1999, 53:1330–1332.

    PubMed  CAS  Google Scholar 

  14. Carter RJ, Hunt MJ, Morton AJ: Environmental stimulation increases survival in mice transgenic for exon 1 of the Huntington’s disease gene. Mov Disord 2000, 15:925–937.

    Article  PubMed  CAS  Google Scholar 

  15. Hockly E, Cordery PM, Woodman B, et al.: Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann Neurol 2002, 51:235–242.

    Article  PubMed  Google Scholar 

  16. Menalled LB, Chesselet MF: Mouse models of Huntington’s disease. Trend Pharmacol Sci 2002, 23:32–39.A nice review of the current mouse models in Huntington’s disease research.

    Article  CAS  Google Scholar 

  17. Jackson GR, Salecker I, Dong X, et al.: Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 1998, 21:633–642.

    Article  PubMed  CAS  Google Scholar 

  18. Faber PW, Alter JR, MacDonald ME, Hart AC: Polyglutaminemediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci U S A 1999, 96:179–184.

    Article  PubMed  CAS  Google Scholar 

  19. Duyao MP, Auerbach AB, Ryan A, et al.: Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science 1995, 269:407–410.

    Article  PubMed  CAS  Google Scholar 

  20. Nasir J, Floresco SB, O’Kusky JR, et al.: Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 1995, 81:811–823.

    Article  PubMed  CAS  Google Scholar 

  21. Zeitlin S, Liu JP, Chapman DL, et al.: Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 1995, 11:155–163.

    Article  PubMed  CAS  Google Scholar 

  22. DiFiglia M, Sapp E, Chase KO, et al.: Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997, 277:1990–1993.

    Article  Google Scholar 

  23. Becher NF, Kotzuk JA, Sharp AH, et al.: Intranuclear neuronal inclusions in Huntington’s disease and DRPLA: correlation between the density of inclusions and IT-15 CAG triplet repeat length. Neurobiol Dis 1998, 4:387–397.

    Article  PubMed  CAS  Google Scholar 

  24. Kahlem P, Terre C, Green H, Djian P: Peptides as glutamine repeats as substrates for transglutaminase-catalyzed crosslinking: relevance to diseases of the nervous system. Proc Natl Acad Sci U S A 1996, 93:14580–14585.

    Article  PubMed  CAS  Google Scholar 

  25. Perutz MF, Johnson T, Suzuki M, Finch JT: Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A 1994, 91:5355–5358.

    Article  PubMed  CAS  Google Scholar 

  26. Sandou F, Finkbeiner S, Devys D, Greenberg ME: Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998, 95:55–66.

    Article  Google Scholar 

  27. Ambrose CM, Duyao MP, Barnes G, et al.: Structure and expression of the Huntington’s disease gene: evidence against simple inactivation due to an expanded CAG repeat. Somatic Cell Mol Genet 1994, 20:27–38.

    Article  PubMed  CAS  Google Scholar 

  28. Gervais FG, Singaraja R, Xanthoudakis S, et al.: Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nature Cell Biol 2002, 4:95–105.

    Article  PubMed  CAS  Google Scholar 

  29. Bence NF, Sampat RM, Kopito RR: Impairent of the ubiquitinproteasome system by protein aggregation. Science 2001, 292:1552–1555.

    Article  PubMed  CAS  Google Scholar 

  30. Luthi-Carter R, Strand A, Peters NL, et al.: Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 2000, 9:1259–1270.A summary of the alterations in gene expression in the R6/2 mouse model of Huntington’s disease using gene chip technology.

    Article  PubMed  CAS  Google Scholar 

  31. Cha JH: Transcriptional dysregulation in Huntington’s disease. Trend Neurosci 2000, 23:387–392.A good review of the evidence for transcriptional dysregulation as an important mechanism in disease pathogenesis.

    Article  PubMed  CAS  Google Scholar 

  32. Steffan JS, Bodai L, Pallos J, et al.: Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001, 413:739–743.An important paper that illustrates the power of invertebrate models to provide important insights into disease pathogenesis and as screens for potential therapeutic agents.

    Article  PubMed  CAS  Google Scholar 

  33. Hackham AS, Singaraja R, Zhang T, et al.: In vitro evidence for both the nucleus and cytoplasmas subcellular sites of pathogenesis in Huntington’s disease. Hum Mol Genet 1999, 8:25–33.

    Article  Google Scholar 

  34. Dragatsis I, Efstratiadis A, Zeitlin A: Mouse mutant embros lacking huntingtin are rescued from lethality by wild-type extraembryonic tissues. Development 1998, 125:1529–1539.

    PubMed  CAS  Google Scholar 

  35. Leavitt BR, Guttman JA, Hodgson JG, et al.: Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo. Am J Hum Genet 2001, 68:313–324.

    Article  PubMed  CAS  Google Scholar 

  36. Zuccato C, Ciammola A, Rigamonti D, et al.: Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 2001, 293:493–498.A key paper that makes a case for a loss of function in Huntington’s disease, as well as providing a hypothesis to explain the selective vulnerability of striatal neurons.

    Article  PubMed  CAS  Google Scholar 

  37. Perry TL, Wright JM, Hansen S, et al.: Failure of aminooxyacetic acid therapy in Huntington disease. Neurology 1980 30(7 Pt 1):772–775.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  39. Tell G, Bohlen P, Schechter PJ, et al.: Treatment of Huntington disease with gamma-acetylenic GABA an irreversible inhibitor of GABA-transaminase: increased CSF GABA and homocarnosine without clinical amelioration. Neurology 1981, 31:207–211.

    PubMed  CAS  Google Scholar 

  40. Kieburtz K, and the Huntington Study Group: A randomized placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease (CARE-HD). Neurology 2001, 57:376–397.

    Google Scholar 

  41. Kremer B, Clark CM, Almqvist EW, et al.: Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial. Neurology 1999, 53:1000–1011.

    PubMed  CAS  Google Scholar 

  42. Rosas HD, Koroshetz WJ, Jenkins BG, et al.: Riluzole therapy in Huntington’s disease (HD). Mov Disord 1999, 14:326–330.

    Article  PubMed  CAS  Google Scholar 

  43. Seppi K, Mueller J, Bodner T, et al.: Riluzole in Huntington’s disease (HD): an open label study with one year follow up. J Neurol 2001, 248:866–869.

    Article  PubMed  CAS  Google Scholar 

  44. Verhagen Metman L, Morris MJ, Farmer C, et al.: Huntington’s disease: a randomized, controlled trial using the NMDAantagonist amantadine. Neurology 2002, 59:694–699.

    Google Scholar 

  45. Ona VO, Li M, Vonsattel JP, et al.: Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 1999, 399:263–267.

    Article  PubMed  CAS  Google Scholar 

  46. Chen M, Ona VO, Li M, et al.: Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000, 6:797–801.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Oregon Health & Science University, Campus Mail OP-32, 3181 SW Sam Jackson Park Road, 97239-3098, Portland, OR, USA

    Penelope Hogarth MD

Authors
  1. Penelope Hogarth MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hogarth, P. Huntington’s disease: A decade beyond gene discovery. Curr Neurol Neurosci Rep 3, 279–284 (2003). https://doi.org/10.1007/s11910-003-0003-3

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-003-0003-3

Keywords

Search

Navigation