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.

帕金森病 （PD） 的特征是黑质中多巴胺能神经元的选择性丢失和 α-突触核蛋白 （α-Syn） 聚集体的积累。然而，调节 α-Syn 聚集和神经元变性的分子机制仍然知之甚少。含有 1 （PM20D1） 基因的肽酶 M20 结构域位于与 PD 遗传相关的 PARK16 基因座内。调节 PM20D1 表达的单核苷酸多态性与 PD 风险的变化有关。据报道，多巴胺 （DA） 代谢和 DA 代谢物可调节 α-Syn 病理。在这里，我们报道了 PM20D1 催化 DA 转化为 N-花生四烯酰多巴胺 （NADA），它与 α-Syn 相互作用并抑制其聚集。同时，NADA 与 α-Syn 原纤维竞争以调节 TRPV4 介导的钙内流和下游磷酸酶，从而减轻 α-Syn 磷酸化。PM20D1 的表达在衰老过程中降低。在突触核蛋白病小鼠模型中过表达 PM20D1 或 NADA 的给药减轻了 α-Syn 病理、多巴胺能神经变性和运动障碍。这些观察结果支持 PM20D1-NADA 通路对 PD 中 α-Syn 病理进展的保护作用。