Parkinson's disease genetic risk converges on Lewy body pathology-associated microglial states

In substantia nigra myeloid cells across the Lewy body continuum, microglia shift from P2RY12-high sensome to an HSP90AA1-high proteostatic-stress state, intensifying at late Braak stages.

• Why it matters: Parkinson’s disease and related -synucleinopathies involve Lewy body spread, but how substantia nigra myeloid cells respond—and which states link to genetic risk—remains unclear.
• What they did: The study profiled 169,799 brain myeloid cells and nuclei from 96 donors (86,427 from the substantia nigra) using SOX10-based oligodendrocyte depletion and CD11b-based myeloid enrichment, integrating with AMP PD for 298,592 profiles.
• The result: HSP60+ proteostatic microglia proportions increased with substantia nigra neuron loss, a rare NUCKS1-high state (~1% of myeloid cells) showed the strongest PD polygenic-risk loading, and rs3732765-A was nominally linked to more P2RY12-high microglia and higher lysosomal program activity.