Low Levels of Mutant Ubiquitin Are Degraded by the Proteasome In Vivo

Paula van Tijn, Marian C. Verhage, Barbara Hobo, Fred W. van Leeuwen, David F. Fischer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The ubiquitin-proteasome system fulfills a pivotal role in regulating intracellular protein turnover. Impairment of this system is implicated in the pathogenesis of neurodegenerative diseases characterized by ubiquitin-containing proteinaceous deposits. UBB+1, a mutant ubiquitin, is one of the proteins accumulating in the neuropathological hallmarks of tauopathies, including Alzheimer's disease, and polyglutamine diseases. In vitro, UBB+1 properties shift from a proteasomal ubiquitin-fusion degradation substrate at low expression levels to a proteasome inhibitor at high expression levels. Here we report on a novel transgenic mouse line (line 6663) expressing low levels of neuronal UBB+1. In these mice, UBB+1 protein is scarcely detectable in the neuronal cell population. Accumulation of UBB+1 commences only after intracranial infusion of the proteasome inhibitors lactacystin or MG262, showing that, at these low expression levels, the UBB+1 protein is a substrate for proteasomal degradation in vivo. In addition, accumulation of the protein serves as a reporter for proteasome inhibition. These findings strengthen our proposition that, in healthy brain, UBB+1 is continuously degraded and disease-related UBB+1 accumulation serves as an endogenous marker for proteasomal dysfunction. This novel transgenic line can give more insight into the intrinsic properties of UBB+1 and its role in neurodegenerative disease.
Original languageEnglish
Pages (from-to)2325-2337
JournalJournal of Neuroscience Research
Issue number11
Publication statusPublished - 15 Aug 2010


  • ubiquitin-proteasome system
  • mutant ubiquitin
  • proteasome inhibitor
  • neurodegenerative disease
  • transgenic mouse model


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