Parkinson’s disease (PD) is characterized by progressive neurodegeneration and chronic neuroinflammation. Microglia are increasingly implicated in disease progression, yet the underlying molecular mechanisms driving their pathogenic functions remain elusive. We identified key microglial genes linked to PD and explore their links to neuroinflammation and neurodegeneration. We obtained the single-cell RNA-seq data from the Gene Expression Omnibus (GEO), and the “Seurat” R package was used for the scRNA-seq analysis. “CellChat” R package was applied for the cell communication analysis. Using the “hdWGCNA” package, a weighted gene co-expression network was constructed to identify module genes, and the key candidate genes were selected by LASSO regression via “glmnet” R package. Functional enrichment of the identified genes was conducted using “clusterProfiler” R package. Finally, molecular docking between its protein structure and compounds was performed using AutoDocktools. In vitro, LPS-stimulated human HMC3 microglia were used to model neuroinflammation, TGFBR1 was overexpressed and its functional impact was evaluated by qPCR, flow cytometry, and cytokine profiling, with SB-431542 inhibition to confirm signaling dependence. Our scRNA-seq analysis of PD samples revealed 10 major cell populations, with microglia displaying an enriched transcriptomic signature in immune- and phagocytosis-associated pathways. Cell communication is facilitated between microglia and neurons/astrocytes by ligand–receptor pairs like APP-CD74. Co-expression network analysis identified a microglia-associated gene module from which we extracted a five-gene signature (DNAJC13, RIN3, SERPINB9, SLC11A1, and TGFBR1) using machine learning. These genes collectively implicated core pathogenic mechanisms, including dysregulated calcium signaling, neuroinflammatory activation, impaired proteostasis, and aberrant cell cycle signaling. Furthermore, molecular docking predicted that diazepam stably binds to TGFBR1 protein with a binding energy of −8.03 kcal/mol, suggesting a potential avenue for therapeutic repurposing targeting this pathway. TGFBR1 was markedly downregulated in LPS-activated HMC3 microglia. Its overexpression reprogrammed microglia toward an anti-inflammatory and reparative phenotype, suppressing iNOS, IL-1β, and IL-6, while inducing Arg1 and IL-4, without affecting proliferation or CD68 expression. This study identified key genes in PD that map to disease-relevant pathways, offering a foundation for future mechanistic studies and emerging therapeutic strategies targeting neuroinflammation.
Liu et al. (Tue,) studied this question.