Human Molecular Genetics, Vol 8, 2377-2385, Copyright © 1999 by Oxford University Press
MK Perez, HL Paulson and RN Pittman
Spinocerebellar ataxia type-3 or Machado-Joseph disease (SCA3/MJD) is a
member of the CAG/polyglutamine repeat disease family. In this family of
disorders, a normally polymorphic CAG repeat becomes expanded, resulting in
expression of an expanded polyglutamine domain in the disease gene product.
Experimental models of polyglutamine disease implicate the nucleus in
pathogenesis; however, the link between intranuclear expression of expanded
polyglutamine and neuronal dysfunction remains unclear. Here we demonstrate
that ataxin-3, the disease protein in SCA3/MJD, adopts a unique
conformation when expressed within the nucleus of transfected cells. The
monoclonal antibody 1C2 is known preferentially to bind expanded
polyglutamine, but we find that it also binds a fragment of ataxin-3
containing a normal glutamine repeat. In addition, expression of ataxin-3
within the nucleus exposes the glutamine domain of the full-length non-
pathological protein, allowing it to bind the monoclonal antibody 1C2.
Fractionation and immunochemical experiments indicate that this novel
conformation of intranuclear ataxin-3 is not due to proteolysis, suggesting
instead that association with nuclear protein(s) alters the structure of
full-length ataxin-3 which exposes the polyglutamine domain. This
conformationally altered ataxin-3 is bound to the nuclear matrix. The
pathological form of ataxin-3 with an expanded polyglutamine domain also
associates with the nuclear matrix. These data suggest that an early event
in the pathogenesis of SCA3/MJD may be an altered conformation of ataxin-3
within the nucleus that exposes the polyglutamine domain.
ARTICLES
Ataxin-3 with an altered conformation that exposes the polyglutamine domain is associated with the nuclear matrix
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6084, USA and
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