Institute of Biomedical Sciences, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), School of Life Sciences, East China Normal University, Shanghai, China.
Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
J Biol Chem. 2022 Nov;298(11):102571. doi: 10.1016/j.jbc.2022.102571. Epub 2022 Oct 7.
The REGγ-20S proteasome is an ubiquitin- and ATP-independent degradation system, targeting selective substrates, possibly helping to regulate aging. The studies we report here demonstrate that aging-associated REGγ decline predisposes to decreasing tau turnover, as in a tauopathy. The REGγ proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGγ-mediated proteasomal degradation of tau was validated in 3- to 12-month-old REGγ KO mice, REGγ KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGγ (REGγ OE) and behavioral abnormalities. Coupled with tau accumulation, we found with REGγ-deficiency, neuron loss, dendrite reduction, tau filament accumulation, and microglial activation are much more prominent in the REGγ KO;PS19 than the PS19 model. Moreover, we observed that the degenerative neuronal lesions and aberrant behaviors were alleviated in REGγ OE;PS19 mice. Memory and other behavior analysis substantiate the role of REGγ in prevention of tauopathy-like symptoms. In addition, we investigated the potential mechanism underlying aging-related REGγ decline. This study provides valuable insights into the novel regulatory mechanisms and potential therapeutic targets for tau-related neurodegenerative diseases.
REGγ-20S 蛋白酶体是一种泛素和 ATP 非依赖性降解系统，靶向选择性底物，可能有助于调节衰老。我们在此报告的研究表明，与衰老相关的 REGγ 下降促使 tau 周转率下降，就像在 tau 病中一样。REGγ 蛋白酶体促进人源和鼠源 tau 的降解，特别是磷酸化 tau 和在细胞质和细胞核之间穿梭的毒性 tau 寡聚物。在 3 至 12 个月大的 REGγ KO 小鼠、REGγ KO;PS19 小鼠以及 PS19 小鼠中，通过 REGγ 介导的 tau 蛋白酶体降解得到了验证，这些小鼠的前脑神经元特异性过表达 REGγ（REGγ OE）并伴有行为异常。随着 REGγ 缺乏，我们发现神经元丢失、树突减少、tau 丝积累和小胶质细胞激活在 REGγ KO;PS19 比 PS19 模型中更为明显，同时还发现 REGγ OE;PS19 小鼠中的退行性神经元损伤和异常行为得到了缓解。记忆和其他行为分析证实了 REGγ 在预防 tau 病样症状中的作用。此外，我们还研究了与衰老相关的 REGγ 下降的潜在机制。这项研究为 tau 相关神经退行性疾病的新型调控机制和潜在治疗靶点提供了有价值的见解。
