Modest proteasomal inhibition by aberrant ubiquitin exacerbates aggregate formation in a Huntington disease mouse model.
UBB(+1), a mutant form of ubiquitin, is both a substrate and an inhibitor of the proteasome which accumulates in the neuropathological hallmarks of Huntington disease (HD). In vitro, expression of UBB(+1) and mutant huntingtin synergistically increase aggregate formation and polyglutamine induced cell death. We generated a UBB(+1) transgenic mouse line expressing UBB(+1) within the neurons of the striatum. In these mice lentiviral driven expression of expanded huntingtin constructs in the striatum results in a significant increase in neuronal inclusion formation. Although UBB(+1) transgenic mice show neither a decreased lifespan nor apparent neuronal loss, they appear to be more vulnerable to toxic insults like expanded polyglutamine proteins due to a modest proteasome inhibition. These findings underscore the relevance of an efficient ubiquitin-proteasome system in HD.
de Pril
Remko
R
Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
Hobo
Barbara
B
van Tijn
Paula
P
Roos
Raymund A C
RA
van Leeuwen
Fred W
FW
Fischer
David F
DF
D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000633:toxicity; D061988:Proteasome Inhibitors; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D061988:Proteasome Inhibitors; C527284:Ubb protein, mouse; D025801:Ubiquitin; C097188:polyglutamine