Molecular chaperones of the Hsp70/40 family protect against the accumulation of mutated or misfolded proteins in part by facilitating their degradation. In the polyglutamine (polyQ) diseases, mutant proteins containing expanded polyQ repeats accumulate in intracellular inclusions and cause neurodegeneration. Although the ubiquitin-proteasome system and chaperones all help protect against accumulation of such toxic proteins, their precise roles are still unclear. Here we observed that the polyQ-expanded mutant ataxin-1 [82Q] was rapidly and selectively degraded in yeast while the wild-type protein [30Q] was stable. The selective degradation of the mutant ataxin-1 required proteasomes, but did not require Ydj1p, an Hsp40 homolog, which is involved in the disaggregation and/or breakdown of a number of misfolded proteins. However, another chaperone Hsp104 promoted degradation of mutant ataxin-1 without influencing the solubility or breakdown of short-lived cell proteins generally. Thus Hsp104-dependent degradation of mutant ataxin-1 may account for the ability of this chaperone to reduce toxicity caused by polyQ-repeat proteins.

• PMID: 19995551
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Lee DH, Goldberg AL

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