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The PM20D1-NADA pathway protects against Parkinson’s disease

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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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Fig. 1: The expression of PM20D1 is decreased during aging and in PD models.
Fig. 2: PM20D1 alleviates α-Syn aggregation and phosphorylation in vivo.
Fig. 3: PM20D1 ameliorates α-Syn pathology and dopaminergic neurodegeneration in a mouse model of synucleinopathy.
Fig. 4: PM20D1 catalyzes the conversion of DA to NADA.
Fig. 5: NADA binds to α-Syn fibrils and alleviates the seeding of α-Syn aggregates.
Fig. 6: NADA attenuates α-Syn PFF-induced TRPV4 activation and calcium overload.
Fig. 7: NADA infusion attenuates α-Syn pathology and motor impairments in vivo.

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Data availability

The authors declare that all the data supporting the findings of this study are available within the article and its supplementary information files (‘Original uncropped membranes’ and ‘supplementary materials’).

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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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  1. These authors contributed equally: Yunying Yang, Sichun Chen, Li Zhang.

Authors and Affiliations

  1. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Yunying Yang, Sichun Chen, Li Zhang, Guoxin Zhang, Yiming Li, Li Zou, Lanxia Meng, Ye Tian, Lijun Dai, Min Xiong, Lina Pan, Jing Xiong & Zhentao Zhang

  2. Department of Nursing, Renmin Hospital of Wuhan University, Wuhan, China

    Yan Liu

  3. Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA

    Liam Chen

  4. Department of Polymer Science, College of Chemistry and Molecular Sciences of Wuhan University, Wuhan, 430060, China

    Hua Hou

  5. Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Zhui Yu

  6. TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430000, China

    Zhentao Zhang

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  13. Jing Xiong
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  14. Liam Chen
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  15. Hua Hou
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  16. Zhui Yu
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  17. Zhentao Zhang
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Contributions

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.

Corresponding author

Correspondence to Zhentao Zhang.

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The authors declare no competing interests.

Ethics

All animal experiments were ethically approved by the Institutional Animal Care and Use Committee (IACUC) of Renmin Hospital of Wuhan University (Approval No. 20210712).

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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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