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 noncanonical proteasome degradation pathway may contribute to the sensorimotor gating deficiency and cognitive disorders in aging mice.
Background: Growing evidence suggest the association between Parkinson’s disease (PD) and diabetes mellitus (DM). On a cellular level, it was proven that long-term elevated levels of glucose might lead to nigrostriatal degeneration in PD models. However, the underlying mechanism is still unclear. Previously, we have elucidated the potential of type 2 diabetes mellitus (T2DM) in facilitating PD progression, involving aggregation of both alpha-synuclein (α-syn) and islet amyloid polypeptide (IAPP) in the pancreatic and brain tissues. However, due to the complicated effect of insulin resistance on PD onset, the actual mechanism of hyperglycemia-induced dopaminergic degeneration remains unknown. Methods: In the present study, we employed the type 1 diabetes mellitus (T1DM) model induced by streptozotocin (STZ) injection, to investigate the direct effect of elevated blood glucose level on nigrostriatal degeneration. Results: We found that STZ treatment induced more severe pathological alterations in the pancreatic islets and T1DM symptoms in α-syn-overexpression mice than that in wild type (WT) mice, one month and three months after STZ injections. Behavioral tests evaluating motor performance confirmed the nigrostriatal degeneration. Furthermore, we observed a marked decrease in dopaminergic profiles and an increase of α-syn accumulation and Serine 129 (S129) phosphorylation in STZ-treated α-syn mice compared with vehicle-treated mice. At last, we observed more severe neuroinflammation in the brain of the STZ-treated α-syn mice.Conclusion: Our results solidify the potential link between DM and PD, providing insights on how hyperglycemia induces nigrostriatal degeneration and contributes to pathogenetic mechanisms in PD.
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