دورية أكاديمية
CDK5-USP30 signaling pathway regulates MAVS-mediated inflammation via suppressing mitophagy in MPTP/MPP + PD model.
| العنوان: | CDK5-USP30 signaling pathway regulates MAVS-mediated inflammation via suppressing mitophagy in MPTP/MPP + PD model. |
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| المؤلفون: | Ren Y; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China; Key Laboratory of Occupational Environment and Health, Guangzhou Occupational Disease Prevention and Treatment Hospital, Guangzhou, China., Wu X; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China., Bai T; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China., Yang N; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China., Yuan Y; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China., Xu L; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China., Wen Y; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China., Wen Y; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China., Wang Z; Key Laboratory of Occupational Environment and Health, Guangzhou Occupational Disease Prevention and Treatment Hospital, Guangzhou, China., Zhou L; Key Laboratory of Occupational Environment and Health, Guangzhou Occupational Disease Prevention and Treatment Hospital, Guangzhou, China., Zou F; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China. Electronic address: zfei@smu.edu.cn., Li W; Department of Occupational Health and Occupational Medicine, Guangdong Province Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province, China. Electronic address: cjlwj@smu.edu.cn. |
| المصدر: | Ecotoxicology and environmental safety [Ecotoxicol Environ Saf] 2024 Jul 01; Vol. 279, pp. 116446. Date of Electronic Publication: 2024 May 20. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7805381 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2414 (Electronic) Linking ISSN: 01476513 NLM ISO Abbreviation: Ecotoxicol Environ Saf Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Amsterdam, Netherlands : Elsevier |
| مواضيع طبية MeSH: | Cyclin-Dependent Kinase 5*/metabolism , Inflammation*/chemically induced , Mitophagy*/drug effects , Signal Transduction*, Animals ; Male ; Mice ; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; Adaptor Proteins, Signal Transducing/metabolism ; Cell Line ; Disease Models, Animal ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Mitochondria/metabolism ; Parkinson Disease |
| مستخلص: | The discovery of MPTP, an industrial chemical and contaminant of illicit narcotics, which causes parkinsonism in humans, non-human primates and rodents, has led to environmental pollutants exposure being convicted as key candidate in Parkinson's disease (PD) pathogenesis. Though MPTP-induced mitochondrial dysfunction and neuroinflammation are mainly responsible for the causative issue of MPTP neurotoxicity, the underlying mechanism involved remains unclear. Here, we reveal a novel signaling mechanism of CDK5-USP30-MAVS regulating MPTP/MPP + induced PD. MPP + (the toxic metabolite of MPTP) treatment not only led to the increased protein levels of USP30 but also to mitophagy inhibition, mitochondrial dysfunction, and MAVS-mediated inflammation in BV2 microglial cells. Both mitophagy stimulation (Urolithin A administration) and USP30 knockdown relieved MAVS-mediated inflammation via restoring mitophagy and mitochondrial function in MPP + -induced cell model. Notably, MPTP/MPP + -induced CDK5 activation regulated USP30 phosphorylation at serine 216 to stabilize USP30. Moreover, CDK5-USP30 pathway promoted MAVS-mediated inflammation in MPTP/MPP + -induced PD model. Inhibition of CDK5 not only had a protective effect on MPP + -induced cell model of PD via suppressing the upregulation of USP30 and the activation of MAVS inflammation pathway in vitro, but also prevented neurodegeneration in vivo and alleviated movement impairment in MPTP mouse model of PD. Overall, our study reveal that CDK5 blocks mitophagy through phosphorylating USP30 and activates MAVS inflammation pathway in MPTP/MPP + -induced PD model, which suggests that CDK5-USP30-MAVS signaling pathway represents a valuable treatment strategy for PD induced by environmental neurotoxic pollutants in relation to MPTP. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: CDK5; MAVS; MPTP; Mitophagy; Parkinson’ disease; USP30 |
| المشرفين على المادة: | 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) 0 (Adaptor Proteins, Signal Transducing) EC 2.7.11.1 (Cyclin-Dependent Kinase 5) EC 3.1.2.- (Usp30 protein, mouse) EC 2.7.11.22 (Cdk5 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20240521 Date Completed: 20240606 Latest Revision: 20240614 |
| رمز التحديث: | 20240614 |
| DOI: | 10.1016/j.ecoenv.2024.116446 |
| PMID: | 38772138 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1090-2414 |
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| DOI: | 10.1016/j.ecoenv.2024.116446 |