Modest proteasomal inhibition by aberrant ubiquitin exacerbates aggregate formation in a Huntington disease mouse model

Remko de Pril, Barbara Hobo, Paula van Tijn, Raymund A. C. Roos, Fred W. van Leeuwen*, David F. Fischer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)


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.
Original languageEnglish
Pages (from-to)281-286
JournalMolecular and Cellular Neuroscience
Issue number3
Publication statusPublished - Mar 2010


  • Polyglutamine disease
  • Ubiquitin proteasome system
  • Neurodegeneration
  • Transgenic mice
  • Inclusions
  • Huntingtin

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