Stage-Specific NF-κB RelA and IRF4 Programs Drive -Synuclein-Induced Disease-Associated Microglia Differentiation
Yang, Y.-T.; Greatti, Y.; Miller, A. T.; Webster, J. M.; Jurkuvenaite, A.; Randolph, J.; Al-Dalahmah, O.; Figge, D. A.; Harms, A. S.
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Microglial activation in response to aggregated -synuclein (-syn) accumulation is a pathological hallmark of Parkinson disease (PD). A distinct activated microglial state, disease-associated microglia (DAM), has been identified across multiple neurodegenerative disorders, including PD. However, the transcriptional and epigenetic programs governing DAM differentiation remain unclear. Here, we show that neuronal -syn overexpression drives progressive microglial state transitions toward DAM, accompanied by increased phagocytic activity and enhanced cytokine and chemokine production. Integrative transcriptomic and chromatin accessibility analyses reveal a hierarchical NF-{kappa}B--AP-1--IRF regulatory program underlying these state transitions. Microglial NF-{kappa}B p65 (RelA) or IRF4 deficiency impairs microglial progression toward DAM, with RelA and IRF4 governing early microglial activation and subsequent DAM differentiation, respectively. Enrichment of NF-{kappa}B, AP-1, and IRF motifs in DAM in human PD supports conservation of this regulatory program across species. Together, our findings establish RelA and IRF4 as sequential, stage-specific regulators that coordinate -syn-induced DAM differentiation in PD.
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