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Neuron. 1997 Aug;19(2):333-44.

Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3.

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Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.


The mechanism of neurodegeneration in CAG/polyglutamine repeat expansion diseases is unknown but is thought to occur at the protein level. Here, in studies of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), we show that the disease protein ataxin-3 accumulates in ubiquitinated intranuclear inclusions selectively in neurons 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. Together with recent findings from transgenic models, our results suggest that intranuclear aggregation of the expanded protein is a unifying feature of CAG/polyglutamine diseases and may be initiated or catalyzed by a glutamine-containing fragment of the disease protein.

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