Parkinson's disease genetic risk converges on Lewy body pathology-associated microglial states
Parkinson's disease (PD) and related α-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, α-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.
Authors
- Josep Oriol Narcís (ORCID: https://orcid.org/0000-0002-4412-5660)
- Alex Tokolyi (ORCID: https://orcid.org/0000-0003-4222-7484)
- Ruth Helen Walker (ORCID: https://orcid.org/0000-0002-8366-072X)
- David A. Knowles (ORCID: https://orcid.org/0000-0002-7408-146X)
- Alice Buonfiglioli (ORCID: https://orcid.org/0000-0002-5550-9360)
- Nienke Mekkes (ORCID: https://orcid.org/0000-0002-5454-0235)
- Joel Blanchard (ORCID: https://orcid.org/0000-0003-3142-2970)
- Emma L Thorn (ORCID: https://orcid.org/0009-0007-3875-7542)
- Daniele Mattei (ORCID: https://orcid.org/0000-0001-6221-9321)
- Inge R. Holtman (ORCID: https://orcid.org/0000-0001-9752-4756)
- Melissa Jill Nirenberg (ORCID: https://orcid.org/0000-0003-3892-6733)
- Towfique Raj (ORCID: https://orcid.org/0000-0002-9355-5704)
- Beomjin Jang (ORCID: https://orcid.org/0009-0008-9056-1480)
- Roy D. Missall
- John F. Crary (ORCID: https://orcid.org/0000-0002-0556-293X)
- Lot D. de Witte (ORCID: https://orcid.org/0000-0002-7235-9958)
- Kosei Hirata (ORCID: https://orcid.org/0009-0007-9027-9277)
- Raphael Kübler (ORCID: https://orcid.org/0000-0001-8448-1021)
- Ariana Chriss (ORCID: https://orcid.org/0000-0002-6319-328X)
- Claudia De Sanctis (ORCID: https://orcid.org/0000-0002-9318-7323)
- Kailash BP (ORCID: https://orcid.org/0000-0002-1501-4881)
- Tarek Khashan
- Felix A. Crary
- Mikaela Rosen Perez
Institutions
- Allen Institute for Brain Science (US)
- University Medical Center Groningen (NL)
- New York Genome Center (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-10-28
- DOI
- https://doi.org/10.64898/2026.10.26.26364188
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- preprint
Funders
- National Institutes of Health
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke