A Transcriptomic Roadmap of Parkinson’s Disease Progression at Single Cell Resolution

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with complex and heterogeneous molecular pathology across the brain. However, the full cellular architecture of PD progression remains unresolved. Here, we present a comprehensive single-nucleus transcriptomic atlas of PD spanning multiple anatomically and clinically relevant brain regions to capture shared and region-influenced transcriptomic features from 97 deeply phenotyped donors, including individuals across the full spectrum of Braak Lewy body stages. Profiling over 2 million nuclei, we define 62 transcriptionally distinct cell subtypes and uncover widespread, cell-type-specific gene expression changes across neurons, glia, and vascular cells. We identify convergent upregulation of stress-responsive transcriptional programs - such as unfolded protein response, DNA damage repair, and autophagy - across multiple cell types, with key regulators including HSF1, MYC, and FOXO3. Integrative analyses link these transcriptional alterations to PD genetic risk, revealing transcription factor to target gene networks enriched for PD GWAS loci in microglia and neuronal subpopulations. To quantify disease burden at cellular resolution, we introduce a transcriptomic pathology score, revealing early-stage activation in neurons and myeloid cells, followed by delayed engagement of vascular populations. We further demonstrate that microglia undergo dynamic, subtype-specific transitions across disease stages, including early adaptive responses and late-phase stress and proliferative programs. Altered cell-cell communication networks, particularly involving myeloid–neuronal signaling, highlight a progressive rewiring of neuroimmune interactions. This atlas provides a foundational resource for understanding PD progression at single-cell resolution, linking genetic risk to dynamic molecular pathology, and illuminating stage-specific targets for therapeutic intervention.