DOI: 10.1073/pnas.182426899. Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity

Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity

10.1073/pnas.182426899

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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.

Bibliography

Sakahira, H., Breuer, P., Hayer-Hartl, M. K., & Hartl, F. U. (2002). Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proceedings of the National Academy of Sciences, 99(suppl_4), 16412â16418.

Authors 4

Hideki Sakahira (first)
Peter Breuer (additional)
Manajit K. Hayer-Hartl (additional)
F. Ulrich Hartl (additional)

References 83 Referenced 180

Dates

Type	When
Created	22 years, 8 months ago (Dec. 10, 2002, 2:03 p.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 4:50 a.m.)
Indexed	1 month, 1 week ago (July 23, 2025, 8:52 a.m.)
Issued	22 years, 8 months ago (Dec. 10, 2002)
Published	22 years, 8 months ago (Dec. 10, 2002)
Published Online	22 years, 8 months ago (Dec. 10, 2002)
Published Print	22 years, 8 months ago (Dec. 10, 2002)

Funders 0

None

BibTeX

@article{Sakahira_2002, title={Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity}, volume={99}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.182426899}, DOI={10.1073/pnas.182426899}, number={suppl_4}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Sakahira, Hideki and Breuer, Peter and Hayer-Hartl, Manajit K. and Hartl, F. Ulrich}, year={2002}, month=dec, pages={16412–16418} }

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  "abstract": "<jats:p>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\u2013proteasome 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.</jats:p>",
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