Low levels of mutant ubiquitin are degraded by the proteasome in vivo

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. © 2010 Wiley‐Liss, Inc.