Identification of immune-mitophagy related gene in PD based on single-cell sequencing and Mendelian randomization

Parkinsons disease (PD) involves dysregulated mitophagy and immuneresponses, though the underlying mechanisms remain unclear. To identify key genes linking these pathways, we integrated single-cell RNA sequencing (GSE157783) with Mendelian randomization(MR) analysis, screening mitophagy-related genes (MRGs) and immune-related genes (IRGs). Differential expression analysis across PD cell subpopulations, combined with MR, revealed four causal genes: SLC11A1and DDX17(protective) and MRAS and PDIA3(risk). These genes were enriched in antigen presentation and calcium signaling pathways and exhibited dynamic expression in astrocytes and microglia during differentiation. Subsequent protein-protein interaction(PPI) network, regulatory (SCENIC), and drug-target analyses further characterized their roles. Validation in MPTP-induced PD mice confirmed behavioral deficits and altered expression of these genes, supporting their functional relevance. Our findings highlight SLC11A1, DDX17, MRAS, and PDIA3 as critical mitophagy-immune hubs in PD, offering mechanistic insights and therapeutic targets. Author SummaryPD is a neurodegenerative disorder linked to mitochondrial dysfunction (mitophagy) and immune dysregulation, yet the interplay between these mechanisms remains poorly understood. Using integrative single-cell sequencing and MR analyses, we identified four key genes-SLC11A1, DDX17, MRAS, and PDIA3-that bridge immune and mitophagy pathways in PD pathogenesis. These genes exhibit causal relationships with PD risk, offering novel insights into diagnostic and therapeutic strategies.