The role of α-synuclein-mediated disease-associated microglia in Parkinson’s disease 3319

Abstract Description Recent advances in single-cell transcriptomics have revealed significant heterogeneity in microglia, brain-resident macrophages that monitor the brain microenvironment. Disease-associated microglia (DAM), a unique transcriptional state, have been implicated in neurodegeneration and aging. Despite their critical role, the signaling pathways regulating DAM development and their function remain unclear. By overexpressing α-synuclein in neurons, our lab established a mouse model of Parkinson’s Disease (PD) that recapitulates microglial activation, immune cell infiltration, and dopaminergic neuron loss. In our model, we observed an expansion of the DAM transcriptional state and successfully characterized DAM accumulation at the protein level throughout PD progression. This accumulation coincides with reduced immune cell infiltration, linking DAM to chronic neuroinflammation. Using scATAC-seq, we identified transcription factors enriched in distinct microglial states: RelA motifs in acutely activated microglia and Irf4 motifs in DAM. Conditional knockout (cKO) of RelA in microglia reduced immune cell infiltration, whereas IRF4 cKO reduced protein expression of Clec7a, a DAM marker. By blocking transitions between different microglial states, our research aims to elucidate the function and role of α-synuclein-mediated DAM in PD progression and potentially establish DAM as a therapeutic target in neurodegenerative disorders. Funding Sources Aligning Science Across Parkinson’s: ASAP Topic Categories Neuroimmunology (NEUR)