title: Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Paulson
authors.forename: M K
authors.initials: MK
authors.lastname: Perez
authors.forename: Y
authors.initials: Y
authors.lastname: Trottier
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: S H
authors.initials: SH
authors.lastname: Subramony
authors.forename: S S
authors.initials: SS
authors.lastname: Das
authors.forename: P
authors.initials: P
authors.lastname: Vig
authors.forename: J L
authors.initials: JL
authors.lastname: Mandel
authors.forename: K H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: R N
authors.initials: RN
authors.lastname: Pittman
mesh_terms: D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017827:Machado-Joseph Disease / Q000378:metabolism*; D008959:Models, Neurological; D011506:Proteins / Q000378:metabolism*
chemical_list: D011506:Proteins; D005973:Glutamine