Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice
Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice
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DOI：
10.1038/npp.2015.285
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发表时间：
2016-04
影响因子：
7.6
通讯作者：
Yiqing Lv;B. Meng;Hao Dong;Tiantian Jing;Nan Wu;Yingying Yang;Lan Huang;R. Moses;B. O’Malley;B. Mei;Xiaotao Li
中科院分区：
文献类型：
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作者：
Yiqing Lv;B. Meng;Hao Dong;Tiantian Jing;Nan Wu;Yingying Yang;Lan Huang;R. Moses;B. O’Malley;B. Mei;Xiaotao Li
Gsk3β调节大脑的某些功能，但维持Gsk3β蛋白稳定性的机制仍不明确。REGγ是一种重要的泛素非依赖性蛋白酶体激活剂，可以降解某些完整的蛋白质，并参与重要的生物过程的调节。在此，我们证明了REGγ在体外和体内都能促进β蛋白的降解。随着GSK3β活性的增加，REGγ基因敲除(REGγ−/−)小鼠在8个月或更大时表现出迟发性的感觉运动门控和认知缺陷，包括工作记忆下降、多动、刻板印象增加、脉冲前抑制缺陷和筑巢障碍。抑制GSK3PPI可以挽救基因敲除小鼠受损的β表型和工作记忆缺陷。此外，我们还发现，在REGγ−/−小鼠脑中，胰酶样蛋白酶体活性随年龄的增长而降低，这可能反映了GSK3β缺乏降解。综上所述，我们的发现揭示了一种新的调控途径，在该途径中，REGγ-蛋白酶体控制GSK3β蛋白的稳定水平。这种非典型蛋白酶体降解途径的功能障碍可能是导致衰老小鼠感觉运动门控缺陷和认知障碍的原因之一。
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.