Pm20d1, or Peptidase M20 Domain Containing 1, is a secreted enzyme that catalyzes the condensation of fatty acids and amino acids into bioactive lipids called N-acyl amino acids (NAAA) [3]. It has been linked to multiple biological processes and diseases. PM20D1 is involved in dopamine (DA) metabolism, where it converts DA to N-arachidonoyl dopamine (NADA), and is associated with the PARK16 locus genetically linked to Parkinson's disease (PD) [1]. In addition, it has been implicated in Alzheimer's disease (AD) as a quantitative trait locus, and is associated with obesity, insulin resistance, and metabolic syndrome [2,3].

In PD, overexpression of PM20D1 in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. NADA, the product of PM20D1-catalyzed reaction, interacts with α-Syn and inhibits its aggregation, and also regulates TRPV4-mediated calcium influx and downstream phosphatases to alleviate α-Syn phosphorylation [1]. In AD, genetically increasing PM20D1 levels decreased AD-related pathologies, while decreasing its levels accelerated them. Only PM20D1 DNA methylation and expression were significantly correlated with the AD-risk associated background among several genes in the PM20D1 QTL region [2]. In obesity-related metabolic disorders, increased serum levels of PM20D1 and its catalytic products NAAA are closely associated with glucose dysregulation, insulin resistance, and metabolic syndrome [3].

In conclusion, PM20D1 plays essential roles in multiple biological processes and disease conditions. Studies using mouse models have revealed its protective role in PD against α-Syn pathology progression, and its contribution to AD-related pathologies. Its association with obesity-related metabolic disorders also highlights its importance in metabolic regulation. These findings from model-based research provide valuable insights into the biological functions of PM20D1 and potential therapeutic targets for these diseases.