CHAPERONE SUPPRESSION OF AGGREGATION AND ALTERED SUBCELLULAR PROTEASOME LOCALIZATION IMPLY PROTEIN MISFOLDING IN SCA1

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodeg enerative disorder caused by expansion of a polyglutamine tract in ata xin-1. In affected neurons of SCA1 patients and transgenic mice, mutan t ataxin-1 accumulates in a single, ubiquitin-positive nuclear inclusi on. In this study, we show that these inclusions stain positively for the 205 proteasome and the molecular chaperone HDJ-2/HSDJ. Similarly, HeLa cells transfected with mutant ataxin-1 develop nuclear aggregates which colocalize with the 205 proteasome and endogenous HDJ-2/HSDJ. O verexpression of wild-type HDJ-2/HSDJ in HeLa cells decreases the freq uency of ataxin-1 aggregation. These data suggest that protein misfold ing is responsible for the nuclear aggregates seen in SCA1, and that o ver-expression of a DnaJ chaperone promotes the recognition of a misfo lded polyglutamine repeat protein, allowing its refolding and/or ubiqu itin-dependent degradation.