CDK5-Mediated Phosphorylation-Dependent Ubiquitination and Degradation of E3 Ubiquitin Ligases GP78 Accelerates Neuronal Death in Parkinson's Disease
| Autor: | Xiang Peng, Hongwei Cai, Pei Zhang, Zheng Zhang, Qingzhi Wang, Ze-Xi Lv, Fengjuan Jiao, Feng He, Bo Tian, Jianguo Yan, Qian Zhang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Neuroscience (miscellaneous) Mitochondrion Protein degradation Cell Line Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Ubiquitin Cyclin-dependent kinase medicine Animals Parkinson Disease Secondary Phosphorylation Neurons biology Cell Death Cyclin-dependent kinase 5 MPTP Neurodegeneration Ubiquitination Cyclin-Dependent Kinase 5 medicine.disease Ubiquitin ligase Cell biology Rats Receptors Autocrine Motility Factor 030104 developmental biology nervous system Neurology chemistry biology.protein Signal Transduction |
| Zdroj: | Molecular neurobiology. 55(5) |
| ISSN: | 1559-1182 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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