Spatiotemporally resolved single-nucleus transcriptomics reveals cellular and regional vulnerability in the midbrain...

Parkinson's disease (PD) is clinically and biologically heterogeneous, and ethnic differences may influence its pathogenesis. However, single-nucleus transcriptomic data from East Asian populations remain limited. Here, we present a spatially resolved single-nucleus transcriptomic atlas of the human substantia nigra (SN) across the PD continuum, control, incidental Lewy body disease (iLBD), and advanced PD, in pathologically confirmed Korean individuals. Our integrative analysis revealed early α-synuclein aggregation in the ventrolateral SN, subtype-selective vulnerability of dopaminergic neurons, and relative preservation of the dorsomedial SN and ventral tegmental area. Trajectory and gene regulatory network analyses of astrocytes and microglia revealed spatiotemporally distinct, disease-associated glial responses, each driven by divergent molecular programs. We also identified two transcriptionally distinct vascular spatial clusters that exhibited differential vulnerability and remodeling. Spatial ligand-receptor analysis of α-synuclein-positive regions revealed intercellular signaling events associated with early pathology, including extracellular matrix remodeling and synaptic adhesion, which were prominent in the iLBD but largely diminished in advanced PD. Integration with PD genome-wide association studies using MAGMA demonstrated differential coupling between genetic risk, spatially resolved cell-state programs, and pseudotime-inferred microglial dynamics across ancestries. This study provides the first high-resolution, spatially mapped single-nucleus transcriptomic resource from an East Asian PD cohort, illuminating early perturbations in the midbrain intercellular and microenvironment that may underlie selective dopaminergic vulnerability and guide the development of ancestry-informed therapeutic strategies.