1. Modest proteasomal inhibition by aberrant ubiquitin exacerbates aggregate formation in a Huntington disease mouse model.
- Author
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de Pril R, Hobo B, van Tijn P, Roos RA, van Leeuwen FW, and Fischer DF
- Subjects
- Animals, Cell Death, Huntingtin Protein, Huntington Disease metabolism, Male, Mice, Mice, Transgenic, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Peptides toxicity, Ubiquitin genetics, Disease Models, Animal, Huntington Disease pathology, Proteasome Inhibitors, Ubiquitin metabolism
- 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., (Copyright 2009 Elsevier Inc. All rights reserved.)
- Published
- 2010
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