Journal Article

Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in <i>Drosophila</i>

H.Y. Edwin Chan, John M. Warrick, Gladys L. Gray-Board, Henry L. Paulson and Nancy M. Bonini

in Human Molecular Genetics

Volume 9, issue 19, pages 2811-2820
Published in print November 2000 | ISSN: 0964-6906
Published online November 2000 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/9.19.2811
Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila

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At least eight dominant human neurodegenerative diseases are due to the expansion of a polyglutamine within the disease proteins. This confers toxicity on the proteins and is associated with nuclear inclusion formation. Recent findings indicate that molecular chaperones can modulate polyglutamine pathogenesis, but the basis of polyglutamine toxicity and the mechanism by which chaperones suppress neurodegeneration remains unknown. In a Drosophila disease model, we demonstrate that chaperones show substrate specificity for polyglutamine protein, as well as synergy in suppression of neurotoxicity. Our analysis also reveals that chaperones alter the solubility properties of the protein, indicating that chaperone modulation of neurodegeneration in vivo is associated with altered biochemical properties of the mutant polyglutamine protein. These findings have implications for these and other human neurodegenerative diseases associated with abnormal protein aggregation.

Journal Article.  7428 words.  Illustrated.

Subjects: Genetics and Genomics

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