Spatiotemporally resolved single-nucleus transcriptomics reveals cellular and regional vulnerability in the midbrain in Parkinson’s disease
5 affiliations
- 1Department of Pathology, Seoul National University Hospital, College of Medicine, Seoul, Republic of Korea
- 2Brain Bank, Seoul National University Hospital, Seoul, Republic of Korea
- 3School of Systems Biomedical Science, Soongsil University, Seoul, Republic of Korea
- 4Department of Bioinformatics, Soongsil University, Seoul, Republic of Korea
- 5Neuroscience Research Institute, Seoul National University, College of Medicine, Seoul, Republic of Korea
Abstract
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.
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BibTeX
@article{yoo2026spatiotemporally,
title = {{Spatiotemporally resolved single-nucleus transcriptomics reveals cellular and regional vulnerability in the midbrain in Parkinson’s disease}},
author = {Sooyeon Yoo and Kwanghoon Lee and Junseo Seo and Hwisoo Choi and Seong-Ik Kim and Junyoung Chang and Yu-Mi Shim and Junil Kim and Jae-Kyung Won and Sung-Hye Park},
journal = {Signal Transduction and Targeted Therapy},
year = {2026},
month = oct,
doi = {10.1038/s41392-026-02794-2},
url = {https://doi.org/10.1038/s41392-026-02794-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Spatiotemporally resolved single-nucleus transcriptomics reveals cellular and regional vulnerability in the midbrain in Parkinson’s disease
AU - Sooyeon Yoo
AU - Kwanghoon Lee
AU - Junseo Seo
AU - Hwisoo Choi
AU - Seong-Ik Kim
AU - Junyoung Chang
AU - Yu-Mi Shim
AU - Junil Kim
AU - Jae-Kyung Won
AU - Sung-Hye Park
PY - 2026
DA - 2026/10/26
JO - Signal Transduction and Targeted Therapy
DO - 10.1038/s41392-026-02794-2
UR - https://doi.org/10.1038/s41392-026-02794-2
AB - 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.
SN - 2095-9907
SN - 2059-3635
ER -