Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease

Polyglutamine (polygln) diseases are a group of inherited neurodegenerative disorders characterized by protein misfolding and aggregation. Here, we in vestigate the role in polygln disease of heat shock proteins (Hsps), the ma jor class of molecular chaperones responsible for modulating protein foldin g in the cell. In transfected COS7 and PC12 neural cells, we show that Hsp4 0 and Hsp70 chaperones localize to intranuclear aggregates formed by either mutant ataxin-3, the disease protein in spinocerebellar ataxia type 3/Mach ado-Joseph disease (SCA3/MJD), or an unrelated green fluorescent protein fu sion protein containing expanded polygln. We further demonstrate that expre ssion of expanded polygln protein elicits a stress response in cells as man ifested by marked induction of Hsp70. Studies of SCA3/MJD disease brain con firm these findings, showing localization of Hsp40 and, less commonly, Hsp7 0 chaperones to intranuclear ataxin-3 aggregates. In transfected cells, ove rexpression of either of two Hsp40 chaperones, the DNAJ protein homologs HD J-1 and HDJ-2, suppresses aggregation of truncated or full-length mutant at axin-3. Finally, we extend these studies to a PC12 neural model of polygln toxicity in which we demonstrate that overexpression of HDJ-1 suppresses po lygln aggregation with a parallel decrease in toxicity. These results sugge st that expanded polygln protein induces a stress response and that specifi c molecular chaperones may aid the handling of misfolded or aggregated poly gln protein in neurons. This study has therapeutic implications because it suggests that efforts to increase chaperone activity may prove beneficial i n this class of diseases.