Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REG as a therapeutic target

Bett, J.S., Goellner, G.M., Woodman, B., Pratt, G., Rechsteiner, M. and Bates, G.P. (2006) Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REG as a therapeutic target. Human Molecular Genetics, 15(1), pp. 33-44. (doi:10.1093/hmg/ddi423)

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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 proteasomes. 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 REGγ could contribute to UPS impairment in polyglutamine diseases by suppressing the proteasomal catalytic sites responsible for cleaving Gln–Gln bonds. Capping of proteasomes with REGγ could therefore contribute to a potential ‘clogging’ of the proteasome by pathogenic polyglutamines. We show here that genetic reduction of REGγ 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-old R6/2 brains relative to non-R6/2, irrespective of REGγ levels. However, assays of 26S proteasome activity in mouse brain extracts reveal no difference in proteolytic activity regardless of R6/2 or REGγ genotype. These findings suggest that REGγ 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bett, Dr John
Authors: Bett, J.S., Goellner, G.M., Woodman, B., Pratt, G., Rechsteiner, M., and Bates, G.P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Copyright Holders:Copyright © 2005 The Authors
First Published:First published in Human Molecular Genetics 15(1):33-44
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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