Skip to main content

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.

  • Review Article
  • Published:

Therapeutic opportunities in polyglutamine disease

Nature Medicine volume 7, pages 419–423 (2001)Cite this article

Abstract

Polyglutamine diseases comprise a class of familial neurodegenerative disorders caused by expression of proteins containing expanded polyglutamine tracts. Great progress has been made in elucidating the molecular mechanisms contributing to polyglutamine pathology, and in identifying potential drug targets. Although much remains to be learned, these advances provide an opportunity for rational approaches to target-based drug discovery.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: In vitro assay systems for polyglutamine disease drug discovery.

Stephen Horwitz

Figure 2: The drug-discovery pipeline for potential therapeutics for the treatment of polyglutamine disease.

Stephen Horwitz

Similar content being viewed by others

References

  1. Zoghbi, H.Y. & Orr, H.T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247 (2000).

    Article  CAS  Google Scholar 

  2. Cummings, C.J. et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature Genet. 19, 148–154 (1998).

    Article  CAS  Google Scholar 

  3. Chai, Y., Koppenhafer, S.L., Shoesmith, S.J., Perez, M.K. & Paulson, H.L. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum. Mol. Genet. 8, 673–682 (1999).

    Article  CAS  Google Scholar 

  4. Stenoien, D.L. et al. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum. Mol. Genet. 8, 731–741 (1999).

    Article  CAS  Google Scholar 

  5. Chai, Y., Koppenhafer, S.L., Bonini, N.M. & Paulson, H.L. Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J. Neurosci. 19, 10338–10347 (1999).

    Article  CAS  Google Scholar 

  6. Kobayashi, Y. et al. Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J. Biol. Chem. 275, 8772–8778 (2000).

    Article  CAS  Google Scholar 

  7. Muchowski, P.J. et al. Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. USA 97, 7841–7846 (2000).

    Article  CAS  Google Scholar 

  8. Satyal, S.H. et al. Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 97, 5750–5755 (2000).

    Article  CAS  Google Scholar 

  9. Fernandez-Funez, P. et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106 (2000).

    Article  CAS  Google Scholar 

  10. Warrick, J.M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nature Genet. 23, 425–428 (1999).

    Article  CAS  Google Scholar 

  11. Kazemi-Esfarjani, P. & Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837–1840 (2000).

    Article  CAS  Google Scholar 

  12. Wyttenbach, A. et al. Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Proc. Natl. Acad. Sci. USA 97, 2898–2903 (2000).

    Article  CAS  Google Scholar 

  13. Alves-Rodrigues, A., Gregori, L. & Figueiredo-Pereira, M.E. Ubiquitin, cellular inclusions and their role in neurodegeneration. Trends Neurosci. 21, 516–20 (1998).

    Article  CAS  Google Scholar 

  14. Paulson, H.L. Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold. Am. J. Hum. Genet. 64, 339–345 (1999).

    Article  CAS  Google Scholar 

  15. Cummings, C.J. et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24, 879–892 (1999).

    Article  CAS  Google Scholar 

  16. Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M.E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).

    Article  CAS  Google Scholar 

  17. Li, X.J. et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378, 398–402 (1995).

    Article  CAS  Google Scholar 

  18. Kalchman, M.A. et al. HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane- associated huntingtin in the brain. Nature Genet. 16, 44–53 (1997).

    Article  CAS  Google Scholar 

  19. Sittler, A. et al. SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol. Cell 2, 427–436 (1998).

    Article  CAS  Google Scholar 

  20. Faber, P.W. et al. Huntingtin interacts with a family of WW domain proteins. Hum. Mol. Genet. 7, 1463–1474 (1998).

    Article  CAS  Google Scholar 

  21. Young, E.T., Sloan, J.S. & Van Riper, K. Trinucleotide repeats are clustered in regulatory genes in Saccharomyces cerevisiae. Genetics 154, 1053–1068 (2000).

    CAS  PubMed Central  Google Scholar 

  22. Perez, M.K. et al. Recruitment and the role of nuclear localization in polyglutamine- mediated aggregation. J. Cell. Biol. 143, 1457–1470 (1998).

    Article  CAS  Google Scholar 

  23. Boutell, J.M. et al. Aberrant interactions of transcriptional repressor proteins with the Huntington's disease gene product, huntingtin. Hum. Mol. Genet. 8, 1647–1655 (1999).

    Article  CAS  Google Scholar 

  24. Kazantsev, A., Preisinger, E., Dranovsky, A., Goldgaber, D. & Housman, D. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc. Natl. Acad. Sci. USA 96, 11404–11409 (1999).

    Article  CAS  Google Scholar 

  25. Steffan, J.S. et al. The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc. Natl. Acad. Sci. USA 97, 6763–6768 (2000).

    Article  CAS  Google Scholar 

  26. McCampbell, A. et al. CREB-binding protein sequestration by expanded polyglutamine. Hum. Mol. Genet. 9, 2197–2202 (2000).

    Article  CAS  Google Scholar 

  27. Shimohata, T. et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nature Genet. 26, 29–36 (2000).

    Article  CAS  Google Scholar 

  28. Cha, J.J. Transcriptional dysregulation in Huntington's disease. Trends Neurosci. 23, 387–392 (2000).

    Article  CAS  Google Scholar 

  29. Lin, X., Antalffy, B., Kang, D., Orr, H.T. & Zoghbi, H.Y. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1 [see comments]. Nature Neurosci. 3, 157–163 (2000).

    Article  CAS  Google Scholar 

  30. Luthi-Carter, R. et al. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum. Mol. Genet. 9, 1259–1271 (2000).

    Article  CAS  Google Scholar 

  31. Coyle, J.T. & Schwarcz, R. Lesions of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature 263, 244–246 (1976).

    Article  CAS  Google Scholar 

  32. McGeer, E.G. & McGeer, P.L. Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic acid and kainic acids. Nature 263, 517–519 (1976).

    Article  CAS  Google Scholar 

  33. Brouillet, E., Conde, F., Beal, M.F. & Hantraye, P. Replicating Huntington's disease phenotype in experimental animals. Prog. Neurobiol. 59, 427–468 (1999).

    Article  CAS  Google Scholar 

  34. Coyle, J.T. & Puttfarcken, P. Oxidative stress, glutamate and neurodegenerative disorders. Science 262, 689–695 (1993).

    Article  CAS  Google Scholar 

  35. Greene, J.G., Porter, R.H., Eller, R.V. & Greenamyre, J.T. Inhibition of succinate dehydrogenase by malonic acid produces an “excitotoxic” lesion in rat striatum. J. Neurochem. 61, 1151–1154 (1993).

    Article  CAS  Google Scholar 

  36. Ferrante, R.J. et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J. Neurosci. 20, 4389–4397 (2000).

    Article  CAS  Google Scholar 

  37. Kieburtz, K. Antiglutamate therapies in Huntington's disease. J. Neural. Transm. Suppl. 55, 97–102 (1999).

    CAS  Google Scholar 

  38. Kremer, B. et al. Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial. Neurology 53, 1000–1011 (1999).

    Article  CAS  Google Scholar 

  39. Murman, D.L. et al. Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease. Neurology 49, 153–161 (1997).

    Article  CAS  Google Scholar 

  40. Shoulson, I. et al. A controlled clinical trial of baclofen as protective therapy in early Huntington's disease. Ann. Neurol. 25, 252–259 (1989).

    Article  CAS  Google Scholar 

  41. McGeer, P.L. & McGeer, E.G. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res. Brain Res. Rev. 21, 195–218. (1995).

    Article  CAS  Google Scholar 

  42. Singhrao, S.K., Neal, J.W., Morgan, B.P. & Gasque, P. Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease. Exp. Neurol. 159, 362–376 (1999).

    Article  CAS  Google Scholar 

  43. Freeman, T.B. et al. Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. Proc. Natl. Acad. Sci. USA 97, 13877–13882 (2000).

    Article  CAS  Google Scholar 

  44. Lim, G.P. et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's disease. J. Neurosci. 20, 5709–5714 (2000).

    Article  CAS  Google Scholar 

  45. Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421 (2000).

    Article  CAS  Google Scholar 

  46. Wellington, C.L. & Hayden, M.R. Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches. Clin. Genet. 57, 1–10 (2000).

    Article  CAS  Google Scholar 

  47. Dragunow, M. et al. In situ evidence for DNA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Neuroreport 6, 1053–1057 (1995).

    Article  CAS  Google Scholar 

  48. Ona, V.O. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease [see comments]. Nature 399, 263–267 (1999).

    Article  CAS  Google Scholar 

  49. Hackam, A.S. et al. The influence of huntingtin protein size on nuclear localization and cellular toxicity. J. Cell. Biol . 141, 1097–1105 (1998).

    Article  CAS  Google Scholar 

  50. Wellington, C.L. et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J. Biol. Chem. 273, 9158–9167 (1998).

    Article  CAS  Google Scholar 

  51. Wellington, C.L. et al. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J. Biol. Chem. 275, 19831–19838 (2000).

    Article  CAS  Google Scholar 

  52. Sanchez, I. et al. Caspase-8 is required for cell death induced by expanded polyglutamine repeats [see comments]. Neuron 22, 623–633 (1999).

    Article  CAS  Google Scholar 

  53. Chen, M. et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Med. 6, 797–801 (2000).

    Article  CAS  Google Scholar 

  54. Vigh, L. et al. Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nature Med. 3, 1150–1154 (1997).

    Article  CAS  Google Scholar 

  55. Heiser, V. et al. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. Proc. Natl. Acad. Sci. USA 97, 6739–6744 (2000).

    Article  CAS  Google Scholar 

  56. Marsh, J.L. et al. Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum. Mol. Genet. 9, 13–25 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J.-H. Cha, S. Fields, H. Orr, H. Paulson, E. Signer and A. Strand for critical reading of the manuscript. We also acknowledge the support of the Hereditary Disease Foundation (R.E.H. and J.M.O.) and the Milton Wexler Post-doctoral Fellowship (R.E.H.)

Author information

Authors and Affiliations

  1. Division of Medical Genetics, Department of Medicine, Department of Genetics, University of Washington, Seattle, Washington, USA

    Robert E. Hughes

  2. Clinical Research Division, Pediatric Oncology Division, Fred Hutchinson Cancer Research Center, Children's Hospital and Regional Medical Center, Seattle, Washington, USA

    James M. Olson

Authors
  1. Robert E. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James M. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Robert E. Hughes or James M. Olson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hughes, R., Olson, J. Therapeutic opportunities in polyglutamine disease. Nat Med 7, 419–423 (2001). https://doi.org/10.1038/86486

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/86486

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing