Abstract
Mitochondrial dysfunction plays a pivotal role in the pathogenesis of Parkinson’s disease (PD). As a mitochondrial governor, voltage-dependent anion channel 1 (VDAC1) is critical for cell survival and death signals and implicated in neurodegenerative diseases. However, the mechanisms of VDAC1 regulation are poorly understood and the role of tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase which is enriched in mitochondria, in PD remains unclear. In this study, we found that TRIM31−/− mice developed age associated motor defects and dopaminergic (DA) neurodegeneration spontaneously. In addition, TRIM31 was markedly reduced both in nigrostriatal region of PD mice induced by MPTP and in SH-SY5Y cells stimulated by MPP+. TRIM31 deficiency significantly aggravated DA neurotoxicity induced by MPTP. Mechanistically, TRIM31 interacted with VDAC1 and catalyzed the K48-linked polyubiquitination to degrade it through its E3 ubiquitin ligase activity. In conclusion, we demonstrated for the first time that TRIM31 served as an important regulator in DA neuronal homeostasis by facilitating VDAC1 degradation through the ubiquitin-proteasome pathway. Our study identified TRIM31 as a novel potential therapeutic target and pharmaceutical intervention to the interaction between TRIM31 and VDAC1 may provide a promising strategy for PD.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China Grant No. 81971193, No. 81571171 and No. 81873748, and Cutting Edge Development Fund of Advanced Medical Research Institute awarded to YZ.
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HL, CG and LC designed, supervised the study, revision and final approval of the manuscript. ZZ, XS, and HL wrote the manuscript. ZZ, YW, XS, GH, LY, YL, RZ, TL and QJ performed the experiments and data analysis. YZ, BL and QZ contributed to experimental design and discussion. All the authors have read the manuscript and provided useful comments.
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All animal experiments were performed according to the principles established for the care and use of laboratory animals by the National Institutes of Health and were approved by the Institutional Animal Care and Use Committee of Shandong University (ECSBMSSDU2019-2-25).
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Zhao, Z., Song, X., Wang, Y. et al. E3 ubiquitin ligase TRIM31 alleviates dopaminergic neurodegeneration by promoting proteasomal degradation of VDAC1 in Parkinson’s Disease model. Cell Death Differ 31, 1410–1421 (2024). https://doi.org/10.1038/s41418-024-01334-1
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DOI: https://doi.org/10.1038/s41418-024-01334-1
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