Single-Cell and Mendelian Randomization Analyses Reveal Novel Genetic Risk Genes of Perivascular Macrophages in Parkinson’s Disease

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by progressive neurovascular dysfunction and neuroinflammation, in which perivascular macrophages (PVMs) serve as key immune sentinels that regulate cerebrovascular homeostasis and disease progression. However, the transcriptional remodeling, genetic susceptibility, and functional mechanisms of PVMs in the pathogenesis of PD remain unclear. In this study, we integrated human midbrain single-nucleus RNA sequencing, genetic association datasets, and transcriptomic analyses to characterize PVM alterations in PD. Through multi-omics analyses, including Mendelian randomization, colocalization, and trajectory inference, we identified PD-associated PVM genes and regulatory pathways, which were further validated in a rotenone-induced PD model. We found extensive transcriptional remodeling of PVMs in PD, manifested by inflammatory activation, altered complement signaling, and aberrant neurovascular interactions. Genetic analyses identified HLA-DRA, OSBPL3, and RIN3 as PD-associated PVM genes that were enriched in PVMs and exhibited dynamic changes during disease progression. Functional analyses suggested that these genes are involved in immune regulation, lipid metabolism, and intracellular trafficking. The rotenone-induced model further confirmed the upregulation of Osbpl3 and Rin3. These findings reveal that PVM-centered neurovascular immune remodeling is a feature of PD and identify HLA-DRA, OSBPL3, and RIN3 as candidate genes supported by genetic evidence, linking PVM dysfunction to PD susceptibility.