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Abstract
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.