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