Decoding the multiregional atlas of Parkinson's disease at single-cell resolution

Characterizing the multiregional cellular landscape of Parkinson's disease (PD) is essential for understanding its broad impact beyond the midbrain. To advance that goal, we analyzed single-nucleus RNA sequencing data from over 2.2 million nuclei across five brain regions from 93 donors. Compositional analysis identified region-specific alterations, including a reduction in layer 2/3 excitatory neurons in the primary motor cortex and an expansion of specific astrocyte, microglial and oligodendrocyte precursor subtypes in the dorsal motor nucleus of the vagus (DMNX). Differential expression analysis revealed that while most transcriptional changes are cell-type-specific, a core set of markers including BNIP3L, WSB1 and the non-coding RNA LINC00862 are ubiquitously dysregulated across lineages. Furthermore, glial and vascular populations in the DMNX exhibit convergent transcriptional profiles characterized by mitochondrial dysfunction, neuroinflammation and extracellular matrix remodeling. These results provide a high-resolution characterization of the molecular and cellular changes in PD, demonstrating that disease-associated alterations are highly dependent on the intersection of cell identity and anatomical location.