Stage-Specific NF-κB RelA and IRF4 Programs Drive -Synuclein-Induced Disease-Associated Microglia Differentiation
- 1University of Alabama at Birmingham
Abstract
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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BibTeX
@misc{yang2026stagespecific,
title = {{Stage-Specific NF-κB RelA and IRF4 Programs Drive -Synuclein-Induced Disease-Associated Microglia Differentiation}},
author = {Y.-T. Yang and Y. Greatti and A. T. Miller and J. M. Webster and A. Jurkuvenaite and J. Randolph and O. Al-Dalahmah and D. A. Figge and A. S. Harms},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754514},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754514v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Stage-Specific NF-κB RelA and IRF4 Programs Drive -Synuclein-Induced Disease-Associated Microglia Differentiation
AU - Y.-T. Yang
AU - Y. Greatti
AU - A. T. Miller
AU - J. M. Webster
AU - A. Jurkuvenaite
AU - J. Randolph
AU - O. Al-Dalahmah
AU - D. A. Figge
AU - A. S. Harms
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754514
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754514v1
AB - 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.
ER -