MAFF as a potential novel protective factor against Parkinson's disease: evidence from Mendelian randomization and single-cell RNA sequencing.

BACKGROUND: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Although MAFF may be involved in PD, the mechanisms underlying this association remain unclear. This study aimed to investigate the potential mechanisms of MAFF in PD and identify novel therapeutic targets. METHODS: PD-related datasets were obtained from public databases. The potential mechanisms of MAFF in PD were investigated using comprehensive gene expression profiling, receiver operating characteristic (ROC) analysis, Mendelian randomization (MR), functional enrichment analysis, immune infiltration analysis, drug prediction, molecular docking, and single-cell RNA sequencing (scRNA-seq). RT-qPCR and ELISA were then used to further validate MAFF expression in PD. RESULTS: MAFF was significantly upregulated in PD samples across multiple datasets and in both mouse and clinical samples. ELISA showed significantly increased MAFF expression in serum samples from patients with PD. The area under the curve (AUC) values for MAFF exceeded 0.70 in both datasets, indicating good diagnostic potential. MR analysis suggested a potential causal association between MAFF and PD (OR = 0.9075, 95% CI = 0.8243-0.9990, p = 0.0477). Notably, MAFF was significantly enriched in the MAPK signaling pathway, suggesting its potential involvement in regulating key cellular processes, including inflammation, in PD. In addition, two differentially infiltrating immune cell types were identified, and MAFF was positively correlated with monocytes. Diphenylcyclopropenone showed the highest interaction score with MAFF, and molecular docking indicated binding between MAFF and diphenylcyclopropenone, with a binding energy of -5.5 kcal/mol. Finally, scRNA-seq analysis highlighted the central roles of pericytes and endothelial cells in PD. Pseudotime analysis showed that MAFF was highly expressed during the late differentiation stages of endothelial cells. CONCLUSION: Overall, this study demonstrated that MAFF may play an important role in PD. These findings provide insights into the molecular mechanisms of PD and may support the development of targeted therapeutic strategies.