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.

Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders

Nature volume 421, pages 373–379 (2003)Cite this article

Abstract

The expansion of a CAG repeat coding for polyglutamine in otherwise unrelated gene products is central to eight neurodegenerative disorders including Huntington's disease1. It has been well documented that expanded polyglutamine fragments, cleaved from their respective full-length proteins, form microscopically visible aggregates in affected individuals and in transgenic mice2,3,4,5,6,7. The contribution of polyglutamine oligomers to neurodegeneration, however, is controversial. The azo-dye Congo red binds preferentially to β-sheets containing amyloid fibrils8,9 and can specifically inhibit oligomerization10 and disrupt preformed oligomers. Here we show that inhibition of polyglutamine oligomerization by Congo red prevents ATP depletion and caspase activation, preserves normal cellular protein synthesis and degradation functions, and promotes the clearance of expanded polyglutamine repeats in vivo and in vitro. Infusion of Congo red into a transgenic mouse model of Huntington's disease, well after the onset of symptoms, promotes the clearance of expanded repeats in vivo and exerts marked protective effects on survival, weight loss and motor function. We conclude that oligomerization is a crucial determinant in the biochemical properties of expanded polyglutamine that are central to their chronic cytotoxicity.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Effect of anti-amyloid compounds on cell death induced by polyglutamine.
Figure 2: Selective inhibition of polyglutamine oligomerization and cytotoxicity by Congo red.
Figure 3: FRET assay for polyglutamine oligomerization.
Figure 4: Inhibition of polyglutamine oligomerization prevents abnormal protein recruitment.
Figure 5: Effect of Congo red on polyglutamine turnover.
Figure 6: Effect of Congo red in the transgenic R62 mouse model of Huntington's disease.

References

  1. 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 72, 971–983 (1993)

    Article  Google Scholar 

  2. 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 

  3. Kim, Y. J. et al. Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc. Natl Acad. Sci. USA 98, 12784–12789 (2001)

    Article  ADS  CAS  Google Scholar 

  4. Lunkes, A. et al. Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol. Cell 10, 259–269 (2002)

    Article  CAS  Google Scholar 

  5. Wellington, C. L. et al. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. J. Neurosci. 22, 7862–7872 (2002)

    Article  CAS  Google Scholar 

  6. Perutz, M. Polar zippers: their role in human disease. Protein Sci. 3, 1629–1637 (1994)

    Article  CAS  Google Scholar 

  7. Mangiarini, L. et al. 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 (1996)

    Article  CAS  Google Scholar 

  8. Klunk, W. E., Pettegrew, J. W. & Abraham, D. J. Quantitative evaluation of Congo red binding to amyloid-like proteins with a β-pleated sheet conformation. J. Histochem. Cytochem. 37, 1273–1281 (1989)

    Article  CAS  Google Scholar 

  9. Carter, D. B. & Chou, K. C. A model for structure-dependent binding of Congo red to Alzheimer β-amyloid fibrils. Neurobiol. Aging 19, 37–40 (1998)

    Article  CAS  Google Scholar 

  10. 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  ADS  CAS  Google Scholar 

  11. Caughey, B. & Raymond, G. J. Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells. J. Virol. 67, 643–650 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Howlett, D. R., George, A. R., Owen, D. E., Ward, R. V. & Markwell, R. E. Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer β-amyloid fibril formation. Biochem. J. 343, 419–423 (1999)

    Article  CAS  Google Scholar 

  13. Klunk, W. E., Debnath, M. L. & Pettegrew, J. W. Chrysamine-G binding to Alzheimer and control brain: autopsy study of a new amyloid probe. Neurobiol. Aging 16, 541–548 (1995)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Beal, M. F., Hyman, B. T. & Koroshetz, W. Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci. 16, 125–131 (1993)

    Article  CAS  Google Scholar 

  16. Deckwerth, T. L. & Johnson, E. M. Jr Temporal analysis of events associated with programmed cell death (apoptosis) of sympathetic neurons deprived of nerve growth factor. J. Cell Biol. 123, 1207–1222 (1993)

    Article  CAS  Google Scholar 

  17. Jaattela, M., Wissing, D., Kokholm, K., Kallunki, T. & Egeblad, M. Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J. 17, 6124–6134 (1998)

    Article  CAS  Google Scholar 

  18. 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  ADS  CAS  Google Scholar 

  19. 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 

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

    Article  ADS  CAS  Google Scholar 

  21. Hazeki, N., Tukamoto, T., Goto, J. & Kanazawa, I. Formic acid dissolves aggregates of an N-terminal huntingtin fragment containing an expanded polyglutamine tract: applying to quantification of protein components of the aggregates. Biochem. Biophys. Res. Commun. 277, 386–393 (2000)

    Article  CAS  Google Scholar 

  22. Moulder, K. L., Onodera, O., Burke, J. R., Strittmatter, W. J. & Johnson, E. M. Jr Generation of neuronal intranuclear inclusions by polyglutamine–GFP: analysis of inclusion clearance and toxicity as a function of polyglutamine length. J. Neurosci. 19, 705–715 (1999)

    Article  CAS  Google Scholar 

  23. 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 

  24. Bence, N. F., Sampat, R. M. & Kopito, R. R. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552–1555 (2001)

    Article  ADS  CAS  Google Scholar 

  25. Hurlbert, M. S. et al. Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes. Diabetes 48, 649–651 (1999)

    Article  CAS  Google Scholar 

  26. Farrer, L. A. Diabetes mellitus in Huntington disease. Clin. Genet. 27, 62–67 (1985)

    Article  CAS  Google Scholar 

  27. Li, H., Li, S. H., Johnston, H., Shelbourne, P. F. & Li, X. J. Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nature Genet. 25, 385–389 (2000)

    Article  CAS  Google Scholar 

  28. DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997)

    Article  CAS  Google Scholar 

  29. Onodera, O. et al. Oligomerization of expanded-polyglutamine domain fluorescent fusion proteins in cultured mammalian cells. Biochem. Biophys. Res. Commun. 238, 599–605 (1997)

    Article  CAS  Google Scholar 

  30. Carter, R. J. et al. Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J. Neurosci. 19, 3248–3257 (1999)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Signer, S. Lokey, M. Kirschner, N. Ayad, M. Kobori, O.Gozani, L. Yoo, R. Sanchez-Olea, A. Degterev and R. King for comments; T. Mitchison for advice; M. Takeuchi for technical assistance; and X.-J. Li, A. Kazantsev and C. Cepko for reagents. This work was supported in part by grants from the Hereditary Disease Foundation and the NIH (to J.Y.).

Author information

Author notes

  1. Ivelisse Sánchez

    Present address: Department of Anatomy and Neurobiology, Boston University School of Medicine, 715 Albany Street, L-813, Boston, Massachusetts, 02118, USA

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Ivelisse Sánchez, Christian Mahlke & Junying Yuan

Authors
  1. Ivelisse Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Mahlke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junying Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junying Yuan.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sánchez, I., Mahlke, C. & Yuan, J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373–379 (2003). https://doi.org/10.1038/nature01301

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01301

This article is cited by

Comments

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.

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