Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease.
Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease.
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Cdk5 磷酸化诱导的 SIRT2 核转位促进帕金森病多巴胺能神经元死亡
DOI：
10.1038/s41531-022-00311-0
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发表时间：
2022-04-20
影响因子：
8.7
通讯作者：
Tian, Bo
中科院分区：
文献类型：
--
作者：
Yan, Jianguo;Zhang, Pei;Tan, Jie;Li, Mao;Xu, Xingfeng;Shao, Xiaoyun;Fang, Fang;Zou, Zhenyou;Zhou, Yali;Tian, Bo
nad依赖性蛋白去乙酰化酶Sirtuin 2 （SIRT2）通过多种底物的去乙酰化调节多种细胞通路，在帕金森病（PD）的背景下被广泛研究。尽管几项基于PD的MPTP模型的研究表明SIRT2缺失可以防止多巴胺能神经元的丢失，但SIRT2介导的神经元死亡的确切机制在很大程度上仍不清楚。在这里，我们发现SIRT2敲除可以有效改善PD转基因小鼠模型中的异常行为表型。重要的是，在PD的细胞和动物模型中，我们观察到SIRT2从细胞质转移到细胞核。此外，SIRT2的核易位促进神经元死亡。此外，周期蛋白依赖性激酶5 （Cdk5）介导的SIRT2在Ser331和Ser335位点的磷酸化似乎是这种核易位所必需的。综上所述，这些结果提供了通过cdk5依赖的SIRT2核胞质穿梭来调控PD进展过程中神经元死亡的机制。
NAD-dependent protein deacetylase Sirtuin 2 (SIRT2), which regulates several cellular pathways by deacetylating multiple substrates, has been extensively studied in the context of Parkinson’s disease (PD). Although several studies based on the MPTP model of PD show that SIRT2 deletion can protect against dopaminergic neuron loss, the precise mechanisms of SIRT2-mediated neuronal death have largely remained unknown. Here, we show that SIRT2 knockout can effectively ameliorate anomalous behavioral phenotypes in transgenic mouse models of PD. Importantly, in both cellular and animal models of PD, it was observed that SIRT2 translocates from the cytoplasm to the nucleus. Further, the nuclear translocation of SIRT2 promotes neuronal death. Moreover, the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of SIRT2 at the Ser331 and Ser335 sites appears to be necessary for such nuclear translocation. Taken together, the results provide insights into the mechanisms involved in the regulation of neuronal death during PD progression via the Cdk5-dependent nuclear–cytoplasmic shuttling of SIRT2.
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影响因子：
4.3
作者：
Inoue, Toshiaki;Hiratsuka, Masaharu;Oshimura, Mitsuo
通讯作者：
Oshimura, Mitsuo
影响因子：
14.9
作者：
Obenauer, JC;Cantley, LC;Yaffe, MB
通讯作者：
Yaffe, MB
影响因子：
4.5
作者：
Grabowska W;Sikora E;Bielak-Zmijewska A
通讯作者：
Bielak-Zmijewska A
影响因子：
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作者：
Mazzocchi, Martina;Collins, Louise M;O'Keeffe, Gerard W
通讯作者：
O'Keeffe, Gerard W
影响因子：
56.9
作者：
Outeiro, Tiago Fleming;Kontopoulos, Eirene;Kazantsev, Aleksey G.
通讯作者：
Kazantsev, Aleksey G.