{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "University of Alabama at Birmingham"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "Y.-T. Yang"
    },
    {
      "name": "Y. Greatti"
    },
    {
      "name": "A. T. Miller"
    },
    {
      "name": "J. M. Webster"
    },
    {
      "name": "A. Jurkuvenaite"
    },
    {
      "name": "J. Randolph"
    },
    {
      "name": "O. Al-Dalahmah"
    },
    {
      "name": "D. A. Figge"
    },
    {
      "affs": [
        0
      ],
      "name": "A. S. Harms"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dtbbsbw7s3wsk.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.25.754514",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754514v1.full",
  "id": "dtbbsbw7s3wsk",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754514v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2808|Neuroinflammation and Neurodegeneration Mechanisms"
    ]
  ],
  "openalex": "W7215111286",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754514v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-25",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/dtbbsbw7s3wsk.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:33Z",
      "native_id": "10.64898/2026.09.25.754514",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754514v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Stage-Specific NF-κB RelA and IRF4 Programs Drive -Synuclein-Induced Disease-Associated Microglia Differentiation",
  "title_text": "Stage-Specific NF-κB RelA and IRF4 Programs Drive -Synuclein-Induced Disease-Associated Microglia Differentiation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:33Z",
  "url": "https://research.draconitic.com/paper/dtbbsbw7s3wsk",
  "venue": "bioRxiv",
  "versions": []
}