Abstract
Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-Syn) aggregates. However, the molecular mechanisms regulating α-Syn aggregation and neuronal degeneration remain poorly understood. The peptidase M20 domain containing 1 (PM20D1) gene lies within the PARK16 locus genetically linked to PD. Single nucleotide polymorphisms regulating PM20D1 expression are associated with changed risk of PD. Dopamine (DA) metabolism and DA metabolites have been reported to regulate α-Syn pathology. Here we report that PM20D1 catalyzes the conversion of DA to N-arachidonoyl dopamine (NADA), which interacts with α-Syn and inhibits its aggregation. Simultaneously, NADA competes with α-Syn fibrils to regulate TRPV4-mediated calcium influx and downstream phosphatases, thus alleviating α-Syn phosphorylation. The expression of PM20D1 decreases during aging. Overexpression of PM20D1 or the administration of NADA in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. These observations support the protective effect of the PM20D1-NADA pathway against the progression of α-Syn pathology in PD.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No. 82271447, 81771382, China), the National Key Research and Development Program of China (2019YFE0115900, China), the Innovative Research Groups of Hubei Province (2022CFA026, China), and the ‘New 20 Terms of Universities in Jinan’ grant (No. 202228022).
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Professor Zhentao Zhang performed conceptualization and funding acquisition, provided supervision and managed the project; Dr. Yunying Yang, Li Zhang and Sichun Chen designed and conducted the experiments and wrote the paper; Dr. Sichun Chen, Professor Hua Hou, Dr. Guoxin Zhang, Yan Liu, Yiming Li, Li Zou, Ye Tian, Lijun Dai, Min Xiong and Lina Pan contributed to the development of the methodology, data curation and visualization; Professor Lanxia Meng, Jing Xiong, Liam Chen and Zhui Yu performed the data analysis, manuscript review and editing.
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Yang, Y., Chen, S., Zhang, L. et al. The PM20D1-NADA pathway protects against Parkinson’s disease. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01356-9
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DOI: https://doi.org/10.1038/s41418-024-01356-9