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.

Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats

Abstract

Neurodegenerative diseases resulting from expanded repeat sequences of glutamine residues are associated with the formation of protein aggregates in the cell nuclei of the affected neurons, but whether these are pathogenic is controversial. Recent observations indicate that the ages of onset of these diseases are exponential functions of the repeat lengths and that the probability of neural death is constant with time. The only process known to us that could give rise to such behaviour is nucleation of the aggregates.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Aggregation from several nuclei of the exon-1 product of the Huntington's disease gene with a repeat of 47 glutamine residues, tagged with a fluorescent protein of relative molecular mass 26,000, and expressed in a single COS-1 cell.

Image courtesy of A. Kazantsev, E. Preisinger and D. Ho.

References

  1. Gusella, J. F. & Macdonald, M. E. Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nature Rev. Neurosci. 1, 109– 115 (2000).

    CAS  Article  Google Scholar 

  2. Perutz, M. F., Johnston, T., Suzuki, M. & Finch, J. T. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc. Natl Acad. Sci. USA 91, 5355– 5358 (1994).

    ADS  CAS  Article  Google Scholar 

  3. Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537– 548 (1997).

    CAS  Article  Google Scholar 

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

    Article  Google Scholar 

  5. Clarke, G. et al. A one-hit model of cell death in inherited neuronal degenerations. Nature 406, 195– 199 (2000).

    ADS  CAS  Article  Google Scholar 

  6. Mullins, J. W. Crystallisation 2nd edn (Butterworth, London, 1972).

    Google Scholar 

  7. Skinner, P. J. et al. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389, 971– 974 (1997).

    ADS  CAS  Article  Google Scholar 

  8. 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 aggregates. Cell 95, 55– 66 (1998).

    CAS  Article  Google Scholar 

  9. Kuemmerle, S. et al. Huntingtin aggregates may not predict neuronal death in Huntington's disease. Neurology 46, 842– 849 (1999).

    CAS  Google Scholar 

  10. Carmichael, J. et al. Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease. Proc. Natl Acad. Sci. USA 97, 9701– 9705 (2000).

    ADS  CAS  Article  Google Scholar 

  11. Perutz, M. F. Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends Biochem. Sci. 24, 58– 63 (1999).

    CAS  Article  Google Scholar 

  12. Nucifora, F. C. Jr et al. Interference by huntingtin and atrophin-1 with CPB-mediated transcription leading to cellular toxicity. Science 291, 2423– 2428 (2001).

    ADS  CAS  Article  Google Scholar 

  13. Narain, Y., Wittenbach, A., Rankin, J., Furlong, R. A. & Rubinsztein, D. C. A molecular investigation of true dominance in Huntington's disease. J. Med. Genet. 36, 739– 746 (1999).

    CAS  Article  Google Scholar 

  14. Kazantsev, A. et al. A polypeptide inhibitor of aggregation suppresses pathogenesis in a Drosophila model of polyglutamine repeat disease. Cell (submitted).

  15. Yamamoto, A., Lucas, J. J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57– 66 (2000).

    CAS  Article  Google Scholar 

  16. Scherzinger, E. et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vivo and in vitro. Cell 90, 549– 558 (1997).

    CAS  Article  Google Scholar 

  17. Huang, C. C. et al. Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat. Cell Mol. Genet. 24, 217– 233 (1998).

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perutz, M., Windle, A. Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats. Nature 412, 143–144 (2001). https://doi.org/10.1038/35084141

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35084141

Further reading

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

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