Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Yan J

PROVIDER: S-EPMC9021196 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Yan Jianguo J Zhang Pei P Tan Jie J Li Mao M Xu Xingfeng X Shao Xiaoyun X Fang Fang F Zou Zhenyou Z Zhou Yali Y Tian Bo B

NPJ Parkinson's disease 20220420 1

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 ...[more]

PMID: 35443760

Similar Datasets

Project description:AimsChromosome 9 open reading frame 72 (C9orf72) is one of the most dazzling molecules in neurodegenerative diseases, albeit that its role in Parkinson's disease (PD) remains unknown. This article aimed to explore the potential mechanism of C9orf72 involved in the pathogenesis of PD.MethodsThe expression and phosphorylation levels of C9orf72 were examined by Western blotting, RT-PCR, and immunoprecipitation using PD models. Multiple bioinformatics software was used to predict the potential phosphorylation sites of C9orf72 by Cdk5, followed by verification of whether Cdk5-inhibitor ROSCOVITINE could reverse the degradation of C9orf72 in PD. By constructing the sh-C9orf72-knockdown adenovirus and overexpressing the FLAG-C9orf72 plasmid, the effects of C9orf72 knockdown and overexpression, respectively, were determined. A short peptide termed Myr-C9orf72 was used to verify whether interfering with Cdk5 phosphorylation at the Ser9 site of the C9orf72 protein could alleviate autophagy disorder, neuronal death, and movement disorder in PD models.ResultsThe expression level of the C9orf72 protein was significantly reduced, albeit the mRNA expression was not changed in the PD models. Moreover, the phosphorylation level was enhanced, and its reduction was mainly degraded by the ubiquitin-proteasome pathway. The key nervous system kinase Cdk5 directly phosphorylated the S9 site of the C9orf72 protein, which promoted the degradation of the C9orf72 protein. The knockdown of C9orf72 aggravated autophagy dysfunction and increased neuronal loss and motor dysfunction in substantia nigra neurons of PD mice. The overexpression of C9orf72 alleviated autophagy dysfunction in PD neurons. Specifically, interference with Cdk5 phosphorylation at the S9 site of C9orf72 alleviated autophagy dysfunction, neuronal death, and motor dysfunction mediated by C9orf72 protein degradation during PD.ConclusionsCumulatively, our findings illustrate the importance of the role of C9orf72 in the regulation of neuronal death during PD progression via the Cdk5-dependent degradation.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets