{
  "abstract": "Parkinson's disease (PD) and related -synucleinopathies are defined by the spread of Lewy body (LB) pathology across vulnerable brain regions, yet how substantia nigra (SN) myeloid cells respond remains unresolved. Using SOX10-based oligodendrocyte depletion and CD11b-based myeloid enrichment, we profiled 169,799 brain myeloid cells and nuclei from 96 donors spanning the LB continuum, including 86,427 from the SN, and integrated them with AMP PD for a total of 298,592 profiles. Across eight conserved states, -synucleinopathy is associated with a bidirectional signature: upregulated glycolytic and proteostatic-stress programs alongside downregulated lysosomal and mitochondrial pathways. Microglia shift from P2RY12-high sensome cells toward an HSP90AA1-high proteostatic stress state, a transition that intensifies at late Braak LB stages. Immunohistochemistry confirmed that HSP60+ proteostatic microglia state proportions increase with SN neuron loss. A rare NUCKS1-high state (~1% of myeloid cells), more abundant in late-stage disease, carried the strongest PD polygenic-risk loading. The PD-protective rs3732765-A allele, a microglial cis-eQTL that lowers P2RY12 expression, was nominally associated with a higher proportion of P2RY12-high microglia and higher lysosomal program activity. These findings frame microglial involvement as structured and genetically tractable, nominating the P2RY12 genetic axis and NUCKS1-high microglia for mechanistic studies.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 24,
  "authors": [
    {
      "name": "R. Kübler"
    },
    {
      "name": "D. Mattei"
    },
    {
      "name": "J. O. Narcis"
    },
    {
      "name": "C. De Sanctis"
    },
    {
      "name": "K. Hirata"
    },
    {
      "name": "A. Buonfiglioli"
    },
    {
      "name": "A. Chriss"
    },
    {
      "name": "M. Rosen Perez"
    },
    {
      "name": "F. A. Crary"
    },
    {
      "name": "E. L. Thorn"
    },
    {
      "name": "A. Tokolyi"
    },
    {
      "name": "T. Khashan"
    },
    {
      "name": "R. D. Missall"
    },
    {
      "name": "B. Jang"
    },
    {
      "name": "K. BP"
    },
    {
      "name": "N. J. Mekkes"
    },
    {
      "name": "M. J. Nirenberg"
    },
    {
      "name": "R. H. Walker"
    },
    {
      "name": "D. A. Knowles"
    },
    {
      "name": "I. R. Holtman"
    },
    {
      "name": "L. D. de Witte"
    },
    {
      "name": "J. F. Crary"
    },
    {
      "name": "J. Blanchard"
    },
    {
      "affs": [
        0
      ],
      "name": "T. Raj"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/50xbps2h8adp6.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.26.26364188",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.26.26364188v1.full",
  "id": "50xbps2h8adp6",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.26.26364188v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "2728|Parkinson's Disease Mechanisms and Treatments"
    ]
  ],
  "openalex": "W7224106964",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.26.26364188v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/50xbps2h8adp6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:00Z",
      "native_id": "10.64898/2026.10.26.26364188",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.26.26364188v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Parkinson's disease genetic risk converges on Lewy body pathology-associated microglial states",
  "title_text": "Parkinson's disease genetic risk converges on Lewy body pathology-associated microglial states",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:00Z",
  "url": "https://research.draconitic.com/paper/50xbps2h8adp6",
  "venue": "medRxiv",
  "versions": []
}