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Low levels of mutant ubiquitin are degraded by the proteasome in vivo
Author(s) -
van Tijn Paula,
Verhage Marian C.,
Hobo Barbara,
van Leeuwen Fred W.,
Fischer David F.
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22396
Subject(s) - lactacystin , proteasome , ubiquitin , in vivo , microbiology and biotechnology , proteasome inhibitor , protein degradation , transgene , biology , chemistry , biochemistry , gene , genetics
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.