Hypothesis | Published:

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

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

  2. 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).

  3. 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).

  4. 4

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

  5. 5

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

  6. 6

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

  7. 7

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

  8. 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).

  9. 9

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

  10. 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).

  11. 11

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

  12. 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).

  13. 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).

  14. 14

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

  15. 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).

  16. 16

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

  17. 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).

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Further reading

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.

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.