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Neuropsychopharmacology. 2016 Apr;41(5):1340-9. doi: 10.1038/npp.2015.285. Epub 2015 Sep 15.

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice.

Author information

1
Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
2
Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, China.
3
Department of Physiology and Biophysics, University of California, Irvine, CA, USA.
4
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.

Abstract

GSK3β regulates some functions of the brain, but the mechanisms involved in the maintenance of GSK3β protein stability remain ambiguous. REGγ, 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 REGγ promotes the degradation of GSK3β protein in vitro and in vivo. With increased GSK3β activity, REGγ knockout (REGγ-/-) 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 GSK3β 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 REGγ-/- mice brains, which may be reflective of a lack of degradation of GSK3β. Collectively, our findings reveal a novel regulatory pathway in which the REGγ-proteasome controls the steady-state level of GSK3β protein. Dysfunction in this non-canonical proteasome degradation pathway may contribute to the sensorimotor gating deficiency and cognitive disorders in aging mice.

PMID:
26370326
PMCID:
PMC4793118
DOI:
10.1038/npp.2015.285
[Indexed for MEDLINE]
Free PMC Article

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