The PM20D1-NADA pathway protects against Parkinson’s disease

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation Pub Date : 2024-08-22 DOI:10.1038/s41418-024-01356-9

Yunying Yang, Sichun Chen, Li Zhang, Guoxin Zhang, Yan Liu, Yiming Li, Li Zou, Lanxia Meng, Ye Tian, Lijun Dai, Min Xiong, Lina Pan, Jing Xiong, Liam Chen, Hua Hou, Zhui Yu, Zhentao Zhang

{"title":"The PM20D1-NADA pathway protects against Parkinson’s disease","authors":"Yunying Yang, Sichun Chen, Li Zhang, Guoxin Zhang, Yan Liu, Yiming Li, Li Zou, Lanxia Meng, Ye Tian, Lijun Dai, Min Xiong, Lina Pan, Jing Xiong, Liam Chen, Hua Hou, Zhui Yu, Zhentao Zhang","doi":"10.1038/s41418-024-01356-9","DOIUrl":null,"url":null,"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.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 11","pages":"1545-1560"},"PeriodicalIF":13.7000,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death and Differentiation","FirstCategoryId":"99","ListUrlMain":"https://www.nature.com/articles/s41418-024-01356-9","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文本刊更多论文

PM20D1-NADA通路可预防帕金森病

帕金森病（PD）的特征是黑质中多巴胺能神经元的选择性丧失和α-突触核蛋白（α-Syn）聚集。然而，人们对调节α-Syn聚集和神经元变性的分子机制仍然知之甚少。含肽酶M20结构域1（PM20D1）基因位于与帕金森病有遗传关联的PARK16位点。调节 PM20D1 表达的单核苷酸多态性与 PD 风险的改变有关。据报道，多巴胺（DA）代谢和DA代谢产物可调节α-Syn病理学。在这里，我们报告了 PM20D1 催化 DA 转化为 N-阿拉伯烯酰多巴胺（NADA），NADA 与 α-Syn 相互作用并抑制其聚集。同时，NADA 与 α-Syn 纤维竞争，调节 TRPV4 介导的钙离子流入和下游磷酸酶，从而缓解 α-Syn 磷酸化。在衰老过程中，PM20D1 的表达量会减少。在突触核蛋白病小鼠模型中过表达 PM20D1 或服用 NADA 可减轻α-Syn 病理变化、多巴胺能神经变性和运动障碍。这些观察结果表明，PM20D1-NADA通路对α-Syn病理学在帕金森病中的发展具有保护作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell Death and Differentiation 生物-生化与分子生物学

CiteScore

24.70

自引率

1.60%

发文量

181

审稿时长

3 months

期刊介绍： Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.