A molecular atlas of cellular vulnerability and resilience in the parkinsonian striatum. [snRNA_seq]

The progressive degeneration of dopaminergic projections to the striatum is a key disease mechanism in Parkinson’s disease (PD). To define the cellular landscape in the parkinsonian striatum, we mapped the cellular transcriptome in early and progressive PD mouse models and in human PD stages. Our analyses revealed significant transcriptomic changes across both neuronal and glial populations, with astrocytes and oligodendrocytes exhibiting distinct disease-associated gene expression profiles. Notably, progressive dopamine depletion uncovered differential neuronal vulnerability, identifying eccentric type striatal projection neurons (SPNs) and Chst9-expressing direct pathway SPNs as the most resilient subtypes in mice and humans. This cross-species molecular atlas of the cell-state dynamics in the parkinsonian striatum uncovers the selectively vulnerable and resilient cell types that can inspire new treatment strategies.