Skip to main content
SpringerLink
Log in

Update on huntington’s disease

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

Abstract

Huntington’s disease (HD) is a devastating neurodegenerative disease causing progressive movement disorders, cognitive dysfunction, and behavioral changes. Since the causative mutation of an expanded polyglutamine repeat in the huntingtin gene was identified, significant progress has been achieved in elucidating pathogenic mechanisms. This review summarizes recent developments in evaluating the role of abnormal protein aggregation, transcriptional dysregulation, mitochondrial and bioenergetic dysfunction, excitotoxicity, and abnormal cellular trafficking in the pathogenesis of HD. In addition, although therapeutic options in HD have been limited, progress in developing targeted therapies continues, and these advancements and future directions are reviewed.

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. Biglan KM, Shoulson I: Huntington’s disease. In Parkinson’s Disease and Movement Disorders. Edited by Jankovic J, Tolosa E. Philadelphia: Lippincott Williams & Wilkins; 2002:212–227.

    Google Scholar 

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

  3. Hickey MA, Chesselet MF: The use of transgenic and knock-in mice to study Huntington’s disease. Cytogenet Genome Res 2003, 100:276–286.

    Article  PubMed  CAS  Google Scholar 

  4. Li SH, Li XJ: Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet 2004, 20:146–154.

    Article  PubMed  Google Scholar 

  5. Perutz MF: Polar zippers: their role in human disease. Pharm Acta Helv 1995, 69:213–224.

    Article  PubMed  CAS  Google Scholar 

  6. Kahlem P, Green H, Djian P: Transglutaminase action imitates Huntington’s disease: selective polymerization of Huntingtin containing expanded polyglutamine. Mol Cell 1998, 1:595–601.

    Article  PubMed  CAS  Google Scholar 

  7. Duyao M, Ambrose C, Myers R, et al.: Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 1993, 4:387–392.

    Article  PubMed  CAS  Google Scholar 

  8. 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  PubMed  CAS  Google Scholar 

  9. Kuemmerle S, Gutekunst CA, Klein AM, et al.: Huntington aggregates may not predict neuronal death in Huntington’s disease. Ann Neurol 1999, 46:842–849.

    Article  PubMed  CAS  Google Scholar 

  10. Bence NF, Sampat RM, Kopito RR: Impairment of the ubiquitin-proteasome system by protein aggregation. Science 2001, 292:1552–1555. This shows that mutant huntingtin inhibits the ubiquitin-proteasome system, suggesting a role for abnormal protein processing in HD.

    Article  PubMed  CAS  Google Scholar 

  11. Ravikumar B, Duden R, Rubinsztein DC: Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 2002, 11:1107–1117. This proposes a potential role for authophagic degradation in the pathogenesis of HD.

    Article  PubMed  CAS  Google Scholar 

  12. Sakahira H, Breuer P, Hayer-Hartl MK, Hartl FU: Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Natl Acad Sci U S A 2002, 99(Suppl 4):16412–16418.

    Article  PubMed  CAS  Google Scholar 

  13. Miller VM, Nelson RF, Gouvion CM, et al.: CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. J Neurosci 2005, 25:9152–9161.

    Article  PubMed  CAS  Google Scholar 

  14. Iwata A, Christianson JC, Bucci M, et al.: Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Natl Acad Sci U S A 2005, 102:13135–13140.

    Article  PubMed  CAS  Google Scholar 

  15. Cha JH: Transcriptional dysregulation in Huntington’s disease. Trends Neurosci 2000, 23:387–392.

    Article  PubMed  CAS  Google Scholar 

  16. Zhai W, Jeong H, Cui L, et al.: In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets. Cell 2005, 123:1241–1253. This reports an elegant system to analyze effects of mutant huntingtin on transcriptional repression. They show that effects are polyQ length-dependent and that soluble mutant huntingtin fragments can affect transcriptional regulation.

    Article  PubMed  CAS  Google Scholar 

  17. Cong SY, Pepers BA, Evert BO, et al.: Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. Mol Cell Neurosci 2005, 30:12–23.

    Article  PubMed  CAS  Google Scholar 

  18. Yu ZX, Li SH, Nguyen HP, Li XJ: Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice. Hum Mol Genet 2002, 11:905–914.

    Article  PubMed  CAS  Google Scholar 

  19. Dunah AW, Jeong H, Griffin A, et al.: Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 2002, 296:2238–2243.

    Article  PubMed  CAS  Google Scholar 

  20. Ludolph AC, He F, Spencer PS, et al.: 3-Nitropropionic acid-exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci 1991, 18:492–498.

    PubMed  CAS  Google Scholar 

  21. Browne SE, Beal MF: The energetics of Huntington’s disease. Neurochem Res 2004, 29:531–546.

    Article  PubMed  CAS  Google Scholar 

  22. Nicholls DG, Budd SL, Ward MW, Castilho RF: Excitotoxicity and mitochondria. Biochem Soc Symp 1999, 66:55–67.

    PubMed  CAS  Google Scholar 

  23. Panov AV, Gutekunst CA, Leavitt BR, et al.: Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 2002, 5:731–736. This showed that polyglutamines can directly act on mitochondria to alter metabolism.

    PubMed  CAS  Google Scholar 

  24. Gunawardena S, Goldstein LS: Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways. Arch Neurol 2005, 62:46–51.

    Article  PubMed  Google Scholar 

  25. Chang DT, Rintoul GL, Pandipati S, Reynolds IJ: Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons. Neurobiol Dis 2006, In press. Links huntingtin aggregates to impaired cellular trafficking and impaired mitochondrial function.

  26. Huntington Study Group: A randomized, placebocontrolled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 2001, 57:397–404.

    Google Scholar 

  27. Ryu H, Rosas HD, Hersch SM, Ferrante RJ: The therapeutic role of creatine in Huntington’s disease. Pharmacol Ther 2005, 108:193–207.

    Article  PubMed  CAS  Google Scholar 

  28. Hersch SM, Gevorkian S, Marder K, et al.: Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG. Neurology 2006, 66:250–252.

    Article  PubMed  CAS  Google Scholar 

  29. Puri BK, Leavitt BR, Hayden MR, et al.: Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial. Neurology 2005, 65:286–292.

    Article  PubMed  CAS  Google Scholar 

  30. Van RaamsdonkJM, Pearson J, Rogers DA, et al.: Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease. Exp Neurol 2005, 196:266–272.

    Article  PubMed  Google Scholar 

  31. Giorgini F, Guidetti P, Nguyen Q, et al.: A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet 2005, 37:526–531.

    Article  PubMed  CAS  Google Scholar 

  32. Vecsei L, Beal MF: Huntington’s disease, behavioral disturbances, and kynurenines: preclinical findings and therapeutic perspectives. Biol Psychiatry 1996, 39:1061–1063.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang X, Smith DL, Meriin AB, et al.: A potent small molecule inhibits polyglutamine aggregation in Huntington’s disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci U S A 2005, 102:892–897.

    Article  PubMed  CAS  Google Scholar 

  34. Cleren C, Calingasan NY, Chen J, Beal MF: Celastrol protects against MPTP- and 3-nitropropionic acid-induced neurotoxicity. J Neurochem 2005, 94:995–1004.

    Article  PubMed  CAS  Google Scholar 

  35. Tadros MG, Khalifa AE, Abdel-Naim AB, Arafa HM: Neuroprotective effect of taurine in 3-nitropropionic acid-induced experimental animal model of Huntington’s disease phenotype. Pharmacol Biochem Behav 2005, 82:574–582.

    Article  PubMed  CAS  Google Scholar 

  36. Dedeoglu A, Kubilus JK, Jeitner TM, et al.: Therapeutic effects of cystamine in a murine model of Huntington’s disease. J Neurosci 2002, 22:8942–8950.

    PubMed  CAS  Google Scholar 

  37. Van RaamsdonkJM, Pearson J, Bailey CD, et al.: Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease. J Neurochem 2005, 95:210–220.

    Article  PubMed  Google Scholar 

  38. Pinto JT, Van Raamsdonk JM, Leavitt BR, et al.: Treatment of YAC128 mice and their wild-type littermates with cystamine does not lead to its accumulation in plasma or brain: implications for the treatment of Huntington disease. J Neurochem 2005, 94:1087–1101.

    Article  PubMed  CAS  Google Scholar 

  39. Dubinsky R, Gray C: CYTE-I-HD: Phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington’s disease. Mov Disord 2005, 20:1316–1322.

    Article  PubMed  Google Scholar 

  40. Ravikumar B, Vacher C, Berger Z, 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.

    Article  PubMed  CAS  Google Scholar 

  41. Wang J, Gines S, MacDonald ME, Gusella JF: Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci 2005, 6:1.

    Article  PubMed  Google Scholar 

  42. Steffan JS, Bodai L, Pallos J, et al.: Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001, 413:739–743.

    Article  PubMed  CAS  Google Scholar 

  43. Ferrante RJ, Kubilus JK, Lee J, et al.: Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci 2003, 23:9418–9427.

    PubMed  CAS  Google Scholar 

  44. Gardian G, Browne SE, Choi DK, et al.: Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease. J Biol Chem 2005, 280:556–563.

    PubMed  CAS  Google Scholar 

  45. Hockly E, Richon VM, Woodman B, et al.: Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci U S A 2003, 100:2041–2046.

    Article  PubMed  CAS  Google Scholar 

  46. Yong VW, Wells J, Giuliani F, et al.: The promise of minocycline in neurology. Lancet Neurol 2004, 3:744–751.

    Article  PubMed  Google Scholar 

  47. Thomas M, Ashizawa T, Jankovic J: Minocycline in Huntington’s disease: a pilot study. Mov Disord 2004, 19:692–695.

    Article  PubMed  Google Scholar 

  48. Bonelli RM, Heuberger C, Reisecker F: Minocycline for Huntington’s disease: an open label study. Neurology 2003, 60:883–884.

    PubMed  Google Scholar 

  49. Furtado S, Sossi V, Hauser RA, et al.: Positron emission tomography after fetal transplantation in Huntington’s disease. Ann Neurol 2005, 58:331–337.

    Article  PubMed  Google Scholar 

  50. Dunnett SB, Rosser AE: Cell therapy in Huntington’s disease. NeuroRx 2004, 1:394–405.

    Article  PubMed  Google Scholar 

  51. Harper SQ, Staber PD, He X, et al.: RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A 2005, 102:5820–5825.

    Article  PubMed  CAS  Google Scholar 

  52. Rodriguez-Lebron E, Denovan-Wright EM, Nash K, et al.: Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington’s disease transgenic mice. Mol Ther 2005, 12:618–633.

    Article  PubMed  CAS  Google Scholar 

  53. 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.

    Article  PubMed  CAS  Google Scholar 

  54. Zala D, Bensadoun JC, Pereira de Almeida L, et al.: Long-term lentiviral-mediated expression of ciliary neurotrophic factor in the striatum of Huntington’s disease transgenic mice. Exp Neurol 2004, 185:26–35.

    Article  PubMed  CAS  Google Scholar 

  55. Miller TW, Messer A: Intrabody applications in neurological disorders: progress and future prospects. Mol Ther 2005, 12:394–401.

    Article  PubMed  CAS  Google Scholar 

  56. Wolfgang WJ, Miller TW, Webster JM, et al.: Suppression of Huntington’s disease pathology in Drosophila by human single-chain Fv antibodies. Proc Natl Acad Sci U S A 2005, 102:11563–11568.

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  58. de TommasoM, Di FruscoloO, Sciruicchio V, et al.: Efficacy of levetiracetam in Huntington disease. Clin Neuropharmacol 2005, 28:280–284.

    Article  PubMed  Google Scholar 

  59. Brusa L, Versace V, Koch G, et al.: Improvement of choreic movements by 1Hz repetitive transcranial magnetic stimulation in Huntington’s disease patients. Ann Neurol 2005, 58:655–656.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Pittsburgh Department of Neurology, Pittsburgh Institute for Neurodegenerative Disease, 3501 Fifth Avenue, Suite 7039, 15260, Pittsburgh, PA, USA

    J. Timothy Greenamyre MD, PhD

Authors
  1. Sarah B. Berman MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Timothy Greenamyre MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Timothy Greenamyre MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berman, S.B., Greenamyre, J.T. Update on huntington’s disease. Curr Neurol Neurosci Rep 6, 281–286 (2006). https://doi.org/10.1007/s11910-006-0019-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-006-0019-6

Keywords

Search

Navigation