title: Modest proteasomal inhibition by aberrant ubiquitin exacerbates aggregate formation in a Huntington disease mouse model.
abstract: 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.
authors.affiliation: Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
authors.forename: Remko
authors.initials: R
authors.lastname: de Pril
authors.forename: Barbara
authors.initials: B
authors.lastname: Hobo
authors.forename: Paula
authors.initials: P
authors.lastname: van Tijn
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.forename: Fred W
authors.initials: FW
authors.lastname: van Leeuwen
authors.forename: David F
authors.initials: DF
authors.lastname: Fischer
mesh_terms: 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*
chemical_list: 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