Parkinson's disease genetic risk converges on Lewy body pathology-associated microglial states
- 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
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.
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BibTeX
@misc{kubler2026parkinsons,
title = {{Parkinson's disease genetic risk converges on Lewy body pathology-associated microglial states}},
author = {R. Kübler and D. Mattei and J. O. Narcis and C. De Sanctis and K. Hirata and A. Buonfiglioli and A. Chriss and M. Rosen Perez and F. A. Crary and E. L. Thorn and A. Tokolyi and T. Khashan and R. D. Missall and B. Jang and K. BP and N. J. Mekkes and M. J. Nirenberg and R. H. Walker and D. A. Knowles and I. R. Holtman and L. D. de Witte and J. F. Crary and J. Blanchard and T. Raj},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.26364188},
url = {https://www.medrxiv.org/content/10.64898/2026.10.26.26364188v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Parkinson's disease genetic risk converges on Lewy body pathology-associated microglial states
AU - R. Kübler
AU - D. Mattei
AU - J. O. Narcis
AU - C. De Sanctis
AU - K. Hirata
AU - A. Buonfiglioli
AU - A. Chriss
AU - M. Rosen Perez
AU - F. A. Crary
AU - E. L. Thorn
AU - A. Tokolyi
AU - T. Khashan
AU - R. D. Missall
AU - B. Jang
AU - K. BP
AU - N. J. Mekkes
AU - M. J. Nirenberg
AU - R. H. Walker
AU - D. A. Knowles
AU - I. R. Holtman
AU - L. D. de Witte
AU - J. F. Crary
AU - J. Blanchard
AU - T. Raj
PY - 2026
DA - 2026/10/26
PB - medRxiv
DO - 10.64898/2026.10.26.26364188
UR - https://www.medrxiv.org/content/10.64898/2026.10.26.26364188v1
AB - 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.
ER -