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Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16412-8. Epub 2002 Aug 20.

Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity.

Author information

1
Max-Planck-Institut für Biochemie, Department of Cellular Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany.

Abstract

The formation of insoluble protein aggregates in neurons is a hallmark of neurodegenerative diseases caused by proteins with expanded polyglutamine (polyQ) repeats. However, the mechanistic relationship between polyQ aggregation and its toxic effects on neurons remains unclear. Two main hypotheses have been put forward for how polyQ expansions may cause cellular dysfunction. In one model neurotoxicity results from the ability of polyQ-expanded proteins to recruit other important cellular proteins with polyQ stretches into the aggregates. In the other model, aggregating polyQ proteins partially inhibit the ubiquitin-proteasome system for protein degradation. These two mechanisms are not exclusive but may act in combination. In general, protein misfolding and aggregation are prevented by the machinery of molecular chaperones. Some chaperones such as the members of the Hsp70 family also modulate polyQ aggregation and suppress its toxicity. These recent findings suggest that an imbalance between the neuronal chaperone capacity and the production of potentially dangerous polyQ proteins may trigger the onset of polyQ disease.

PMID:
12189209
PMCID:
PMC139902
DOI:
10.1073/pnas.182426899
[Indexed for MEDLINE]
Free PMC Article

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