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

Yiqing Lv, Bo Meng, Hao Dong, Tiantian Jing, Nan Wu, Yingying Yang, Lan Huang, Robb Moses, Bert W. O'Malley, Bing Mei, Xiaotao Li

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1340-1349
Number of pages10
JournalNeuropsychopharmacology
Volume41
Issue number5
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Fingerprint

Brain Diseases
Proteasome Endopeptidase Complex
Knockout Mice
Sensory Gating
Up-Regulation
Short-Term Memory
Proteolysis
Biological Phenomena
Protein Stability
Brain
Ubiquitin
Trypsin
Proteins
Maintenance
Phenotype
Prepulse Inhibition

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Lv, Y., Meng, B., Dong, H., Jing, T., Wu, N., Yang, Y., ... Li, X. (2016). Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice. Neuropsychopharmacology, 41(5), 1340-1349. https://doi.org/10.1038/npp.2015.285

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice. / Lv, Yiqing; Meng, Bo; Dong, Hao; Jing, Tiantian; Wu, Nan; Yang, Yingying; Huang, Lan; Moses, Robb; O'Malley, Bert W.; Mei, Bing; Li, Xiaotao.

In: Neuropsychopharmacology, Vol. 41, No. 5, 01.04.2016, p. 1340-1349.

Research output: Contribution to journalArticle

Lv, Y, Meng, B, Dong, H, Jing, T, Wu, N, Yang, Y, Huang, L, Moses, R, O'Malley, BW, Mei, B & Li, X 2016, 'Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice', Neuropsychopharmacology, vol. 41, no. 5, pp. 1340-1349. https://doi.org/10.1038/npp.2015.285
Lv, Yiqing ; Meng, Bo ; Dong, Hao ; Jing, Tiantian ; Wu, Nan ; Yang, Yingying ; Huang, Lan ; Moses, Robb ; O'Malley, Bert W. ; Mei, Bing ; Li, Xiaotao. / Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice. In: Neuropsychopharmacology. 2016 ; Vol. 41, No. 5. pp. 1340-1349.
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