Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REGgamma as a therapeutic target.
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 REGgamma could contribute to UPS impairment in polyglutamine diseases by suppressing the proteasomal catalytic sites responsible for cleaving Gln-Gln bonds. Capping of proteasomes with REGgamma could therefore contribute to a potential 'clogging' of the proteasome by pathogenic polyglutamines. We show here that genetic reduction of REGgamma 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 REGgamma levels. However, assays of 26S proteasome activity in mouse brain extracts reveal no difference in proteolytic activity regardless of R6/2 or REGgamma genotype. These findings suggest that REGgamma 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.
Bett
John S
JS
Department of Medical and Molecular Genetics, GKT School of Medicine, King's College London, UK.
Goellner
Geoffrey M
GM
Woodman
Ben
B
Pratt
Gregory
G
Rechsteiner
Martin
M
Bates
Gillian P
GP
D000704:Analysis of Variance; D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D003433:Crosses, Genetic; D017931:DNA Primers; D005106:Exploratory Behavior / Q000502:physiology; D005838:Genotype; D006816:Huntington Disease / Q000378:metabolism*; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D045442:Rotarod Performance Test
D001324:Autoantigens; D017931:DNA Primers; C099558:Ki antigen; D010455:Peptides; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease