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CDK5-Mediated Phosphorylation-Dependent Ubiquitination and Degradation of E3 Ubiquitin Ligases GP78 Accelerates Neuronal Death in Parkinson’s Disease

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Abstract

The molecular mechanisms responsible for the loss of dopaminergic neurons in Parkinson’s disease (PD) remain obscure. Loss of function of E3 ubiquitin ligases is associated with mitochondria dysfunction, dysfunction of protein degradation, and α-synuclein aggregation, which are major contributors to neurodegeneration in PD. Recent research has thus focused on E3 ubiquitin ligase glycoprotein 78 (GP78); however, the role of GP78 in PD pathogenesis remains unclear. Notably, cyclin-dependent kinase 5 (CDK5) controls multiple cellular events in postmitotic neurons, and CDK5 activity has been implicated in the pathogenesis of PD. Thus, we addressed the relationship between CDK5 and GP78 in MPTP-based PD models. We found that GP78 expression is decreased in MPTP-based cellular and animal PD models, and CDK5 directly phosphorylated GP78 at Ser516, which promoted the ubiquitination and degradation of GP78. Importantly, overexpression of GP78 or interference of GP78 Ser516 phosphorylation protected neurons against MPP+-induced cell death. Thus, our research reveals that the CDK5-GP78 pathway is involved in the pathogenesis of PD and could be a novel candidate drug target for the treatment of PD.

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Acknowledgments

This work was supported financially by the National Natural Science Foundation of China (Nos. 31371384 and 31571044 to B.T. and No. 31600821 to P.Z.), Program for New Century Excellent Talents in University (No. NCET-10-0415 to B.T.), and China Postdoctoral Scientific Foundation (No. 2015M582226 to P.Z.).

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  1. Qingzhi Wang and Fengjuan Jiao contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, Tongji Medical School, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, People’s Republic of China

    Qingzhi Wang, Fengjuan Jiao, Pei Zhang, Jianguo Yan, Zheng Zhang, Feng He, Qian Zhang, Zexi Lv, Xiang Peng, Hongwei Cai & Bo Tian

  2. Institute for Brain Research, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei Province, 430030, People’s Republic of China

    Qingzhi Wang, Fengjuan Jiao, Pei Zhang, Jianguo Yan, Zheng Zhang, Feng He, Qian Zhang, Zexi Lv, Xiang Peng, Hongwei Cai & Bo Tian

  3. Medical School, Hubei Polytechnic University, Huangshi, Hubei Province, People’s Republic of China

    Qingzhi Wang

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  1. Qingzhi Wang
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Correspondence to Bo Tian.

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All animal experiments were approved by the Institutional Animal Care and Use Committees of Huazhong University of Science and Technology.

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Wang, Q., Jiao, F., Zhang, P. et al. CDK5-Mediated Phosphorylation-Dependent Ubiquitination and Degradation of E3 Ubiquitin Ligases GP78 Accelerates Neuronal Death in Parkinson’s Disease. Mol Neurobiol 55, 3709–3717 (2018). https://doi.org/10.1007/s12035-017-0579-2

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