Human Molecular Genetics, 2001, Vol. 10, No. 24 2821-2831
© 2001 Oxford University Press
Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex
1Howard Hughes Medical Institute, 2Department of Human Genetics and Neurology, 3Department of Biochemistry, 4Department of Pathology, 5Huntsman Cancer Institute, 6Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112-5331, USA and 7Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UIA), Antwerp, Belgium
Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by ataxia and selective neuronal cell loss caused by the expansion of a translated CAG repeat encoding a polyglutamine tract in ataxin-7, the SCA7 gene product. To gain insight into ataxin-7 function and to decipher the molecular mechanisms of neurodegeneration in SCA7, a two-hybrid assay was performed to identify ataxin-7 interacting proteins. Herein, we show that ataxin-7 interacts with the ATPase subunit S4 of the proteasomal 19S regulatory complex. The ataxin-7/S4 association is modulated by the length of the polyglutamine tract whereby S4 shows a stronger association with the wild-type allele of ataxin-7. We demonstrate that endogenous ataxin-7 localizes to discrete nuclear foci that also contain additional components of the proteasomal complex. Immunohistochemical analyses suggest alterations either of the distribution or the levels of S4 immunoreactivity in neurons that degenerate in SCA7 brains. Immunoblot analyses demonstrate reduced levels of S4 in SCA7 cerebella without evident alterations in the levels of other proteasome subunits. These results suggest a role for S4 and ubiquitin-mediated proteasomal proteolysis in the molecular pathogenesis of SCA7.
+ To whom correspondence should be addressed at: Department of Neurobiology and Anatomy, University of Utah – Building 533, Room 4420, 15 North 2030 East, Salt Lake City, UT 84112-5331, USA. Tel: +1 801 581 3993; Fax: +1 801 585 5597; Email: yinghui@howard.genetics.utah.eduPresent address:Antoni Matilla, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK
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