INTRANUCLEAR INCLUSIONS OF EXPANDED POLYGLUTAMINE PROTEIN IN SPINOCEREBELLAR ATAXIA TYPE-3

The mechanism of neurodegeneration in CAG/polyglutamine repeat expansi on diseases is unknown but is thought to occur at the protein level. H ere, in studies of spinocerebellar ataxia type 3, also known as Machad o-Joseph disease (SCA3/MJD), we show that the disease protein ataxin-3 accumulates in ubiquitinated intranuclear inclusions selectively in n eurons of affected brain regions. We further provide evidence in vitro for a model of disease in which an expanded polyglutamine-containing fragment recruits full-length protein into insoluble aggregates. Toget her with recent findings from transgenic models, our results suggest t hat intranuclear aggregation of the expanded protein is a unifying fea ture of CAG/polyglutamine diseases and may be initiated or catalyzed b y a glutamine-containing fragment of the disease protein.