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Human Molecular Genetics Advance Access published online on November 25, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi423
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© The Author 2005. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received September 22, 2005
Accepted November 10, 2005

Article

Proteasome Impairment does not Contribute to Pathogenesis in R6/2 Huntington's Disease Mice: Exclusion of Proteasome Activator REG{gamma} as a Therapeutic Target

John S. Bett 1, Geoffrey M. Goellner 2, Ben Woodman 1, Gregory Pratt 2, Martin Rechsteiner 2, and Gillian P. Bates 1 *

1 King's College London, Department of Medical and Molecular Genetics, GKT School of Medicine, SE1 9RT, UK
2 Department of Biochemistry, University of Utah School of Medicine, 50 N Medical Drive, Salt Lake City, UT 84132, USA

* To whom correspondence should be addressed.
Gillian P. Bates, E-mail: gillian.bates{at}genetics.kcl.ac.uk


  Abstract

Huntington's disease (HD) is one of a group of neurodegenerative disorders caused by the pathological expansion of a glutamine tract. A hallmark of these so-called polyglutamine diseases is the presence of ubiquitylated inclusion bodies which sequester various components of the 19S and 20S proteasome. In addition, the ubiquitin-proteasome system (UPS) has been shown to be severely impaired in vitro in cells overexpressing mutant huntingtin. Thus, because of its fundamental housekeeping function, impairment of the UPS in neurons could contribute to neurotoxicity. We have recently proposed that the proteasome activator REG{gamma} could contribute to UPS impairment in polyglutamine diseases by suppressing the proteasomal catalytic sites responsible for cleaving Gln-Gln bonds. Capping of proteasomes with REG{gamma} could therefore contribute to a potential "clogging" of the proteasome by pathogenic polyglutamines. We show here that genetic reduction of REG{gamma} has no effect on the well-defined neurological phenotype of R6/2 HD mice, and does not affect inclusion body formation in the R6/2 brain. Surprisingly, we observe increased proteasomal "chymotrypsin-like" activity in 13 week R6/2 brains relative to non-R6/2 irrespective of REG{gamma} levels. However, assays of 26S proteasome activity in mouse brain extracts reveal no difference in proteolytic activity regardless of R6/2 or REG{gamma} genotype. These findings suggest REG{gamma} is not a viable therapeutic target in polyglutamine disease and that overall proteasome function is not impaired by trapped mutant polyglutamine in R6/2 mice.


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