Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease

被引：24

作者：

Yan, Jianguo ^{[1
,2
]}

Zhang, Pei ^{[3
]}

Tan, Jie ^{[2
]}

Li, Mao ^{[1
,2
]}

Xu, Xingfeng ^{[1
,2
]}

Shao, Xiaoyun ^{[2
]}

Fang, Fang ^{[2
]}

Zou, Zhenyou ^{[2
]}

Zhou, Yali ^{[2
,4
]}

Tian, Bo ^{[3
]}

机构：

[1] Guilin Med Univ, Dept Physiol, Fac Basic Med Sci, 1 Zhiyuan Rd, Guilin 541199, Guangxi, Peoples R China

[2] Guilin Med Univ, Guangxi Key Lab Brain & Cognit Neurosci, 1 Zhiyuan Rd, Guilin 541199, Guangxi, Peoples R China

[3] Huazhong Univ Sci & Technol, Tongji Med Sch, Dept Neurobiol, 13 Hangkong Rd, Wuhan 430030, Hubei, Peoples R China

[4] Guilin Med Univ, Dept Microbiol, Fac Basic Med Sci, 1 Zhiyuan Rd, Guilin 541199, Guangxi, Peoples R China

来源：

NPJ PARKINSONS DISEASE | 2022年 / 8卷 / 01期

基金：

中国国家自然科学基金;

关键词：

HISTONE DEACETYLASE; ACTIVATION; PROTECTS; METABOLISM; INHIBITOR; DISCOVERY; TOXICITY; MODELS;

D O I：

10.1038/s41531-022-00311-0

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页数：12

共 42 条

[1] Overexpression of Sirtuin 1 protein in neurons prevents and reverses experimental diabetic neuropathy [J].