| First Author | Lv Y | Year | 2016 |
| Journal | Neuropsychopharmacology | Volume | 41 |
| Issue | 5 | Pages | 1340-9 |
| PubMed ID | 26370326 | Mgi Jnum | J:333879 |
| Mgi Id | MGI:6844061 | Doi | 10.1038/npp.2015.285 |
| Citation | Lv Y, et al. (2016) Upregulation of GSK3beta Contributes to Brain Disorders in Elderly REGgamma-knockout Mice. Neuropsychopharmacology 41(5):1340-9 |
| abstractText | GSK3beta regulates some functions of the brain, but the mechanisms involved in the maintenance of GSK3beta protein stability remain ambiguous. REGgamma, an important proteasome activator for ubiquitin-independent protein degradation, has been shown to degrade certain intact proteins and is involved in the regulation of important biological processes. Here we demonstrate that REGgamma promotes the degradation of GSK3beta protein in vitro and in vivo. With increased GSK3beta activity, REGgamma knockout (REGgamma-/-) mice exhibit late-onset sensorimotor gating and cognitive deficiencies including decreased working memory, hyperlocomotion, increased stereotype, defective prepulse inhibition (PPI), and disability in nest building, at the age of 8 months or older. Inhibition of GSK3beta rescued the compromised PPI phenotypes and working memory deficiency in the knockout mice. Also, we found an age-dependent decrease in the trypsin-like proteasomal activity in REGgamma-/- mice brains, which may be reflective of a lack of degradation of GSK3beta. Collectively, our findings reveal a novel regulatory pathway in which the REGgamma-proteasome controls the steady-state level of GSK3beta protein. Dysfunction in this non-canonical proteasome degradation pathway may contribute to the sensorimotor gating deficiency and cognitive disorders in aging mice. |
