2. Academic Validation
  3. CDK5-USP30 signaling pathway regulates MAVS-mediated inflammation via suppressing mitophagy in MPTP/MPP+ PD model

CDK5-USP30 signaling pathway regulates MAVS-mediated inflammation via suppressing mitophagy in MPTP/MPP+ PD model

  • Ecotoxicol Environ Saf. 2024 Jul 1:279:116446. doi: 10.1016/j.ecoenv.2024.116446.
Yixian Ren 1,  Xian Wu 2,  Tianyao Bai 2,  Nanfei Yang 2,  Yuyu Yuan 2,  Lingling Xu 2,  Yue Wen 2,  Ying Wen 2,  Zhi Wang 3,  Liping Zhou 3,  Fei Zou 4,  Wenjun Li 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Key Laboratory of Occupational Environment and Health, Guangzhou Occupational Disease Prevention and Treatment Hospital, Guangzhou, China.
  • 4 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.
  • 5 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.
PMID: 38772138 DOI: 10.1016/j.ecoenv.2024.116446
Abstract

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.

Keywords

CDK5; MAVS; MPTP; Mitophagy; Parkinson’ disease; USP30.

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