Pm20d1, or peptidase M20 domain containing 1, is a secreted enzyme that catalyzes the condensation of fatty acids and amino acids into bioactive lipids known as N-acyl amino acids (NAAA) [3]. It has been linked to multiple biological processes and diseases. For instance, PM20D1 lies within the PARK16 locus genetically associated with Parkinson's disease (PD), and it is also a quantitative trait locus associated with Alzheimer's disease (AD) [1,2,4]. In the context of metabolism, it has been associated with obesity, insulin resistance, and metabolic syndrome [3].

In PD, overexpression of PM20D1 in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. PM20D1 catalyzes the conversion of dopamine (DA) to N-arachidonoyl dopamine (NADA), which inhibits α-Syn aggregation and phosphorylation [1]. In AD, genetically increasing PM20D1 levels decreased AD-related pathologies in mouse models, while decreasing its levels accelerated these pathologies. Only PM20D1 DNA methylation and expression were significantly correlated with the AD-risk associated background among related genes [2]. In polycystic ovary syndrome-insulin resistance (PCOS-IR), loss of adipocyte PM20D1 aggravated insulin resistance (IR), and quercitrin, by upregulating PM20D1, activated the PI3K/Akt signaling pathway to improve the condition [5].

In conclusion, PM20D1 plays crucial roles in multiple disease areas. In PD, it protects against α-Syn pathology through the PM20D1-NADA pathway. In AD, it contributes to neuroprotection in a particular genetic background. In PCOS-IR, it is involved in regulating lipid metabolism and reproductive function through the PI3K/Akt pathway. Research on PM20D1 using mouse models has provided valuable insights into its functions in these disease processes.

References:

1. Yang, Yunying, Chen, Sichun, Zhang, Li, Yu, Zhui, Zhang, Zhentao. 2024. The PM20D1-NADA pathway protects against Parkinson's disease. In Cell death and differentiation, 31, 1545-1560. doi:10.1038/s41418-024-01356-9. https://pubmed.ncbi.nlm.nih.gov/39174646/

2. Sanchez-Mut, Jose Vicente, Glauser, Liliane, Monk, David, Gräff, Johannes. 2020. Comprehensive analysis of PM20D1 QTL in Alzheimer's disease. In Clinical epigenetics, 12, 20. doi:10.1186/s13148-020-0814-y. https://pubmed.ncbi.nlm.nih.gov/32014019/

3. Yang, Ranyao, Hu, Yue, Lee, Chi Ho, Lam, Karen S L, Xu, Aimin. 2021. PM20D1 is a circulating biomarker closely associated with obesity, insulin resistance and metabolic syndrome. In European journal of endocrinology, 186, 151-161. doi:10.1530/EJE-21-0847. https://pubmed.ncbi.nlm.nih.gov/34757919/

4. Sanchez-Mut, Jose V, Heyn, Holger, Silva, Bianca A, Esteller, Manel, Gräff, Johannes. 2018. PM20D1 is a quantitative trait locus associated with Alzheimer's disease. In Nature medicine, 24, 598-603. doi:10.1038/s41591-018-0013-y. https://pubmed.ncbi.nlm.nih.gov/29736028/

5. Li, Meihe, Gao, Shan, Kang, Minchao, Dang, Huimin, Zheng, Jin. 2023. Quercitrin alleviates lipid metabolism disorder in polycystic ovary syndrome-insulin resistance by upregulating PM20D1 in the PI3K/Akt pathway. In Phytomedicine : international journal of phytotherapy and phytopharmacology, 117, 154908. doi:10.1016/j.phymed.2023.154908. https://pubmed.ncbi.nlm.nih.gov/37321077/