SINGLE-CELL AND SPATIAL TRANSCRIPTOMICS REVEAL NEURONAL AND REGIONAL VULNERABILITY IN THE HUMAN DORSAL STRIATUM IN PARKINSON’S DISEASE

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra and consequent disruption of dorsal striatal circuitry, leading to impaired motor control. While striatal dysfunction is central to PD pathophysiology, the cell-type– and region-specific transcriptional changes underlying this disruption remain incompletely understood.

Using single-cell transcriptomic profiling of the human dorsal striatum, we identified twenty distinct neuronal cell types spanning two neuronal classes, revealing extensive cellular heterogeneity. Differential expression analyses uncovered pronounced dysregulation in specific interneuron populations, including the recently described PTHLH and TAC3 populations, whereas gene module analysis demonstrated that medium spiny neurons (MSNs) are predominantly affected through alterations in coordinated transcriptional programs rather than isolated gene-level changes. Evaluation of transcriptional perturbations across Braak Stages demonstrated that interneuron dysregulation becomes increasingly prominent at later stages of disease progression.

Comparative regional analyses consistently showed higher transcriptional activity and more severe dysregulation in the caudate nucleus relative to the putamen, indicating region-specific vulnerability within the striatum. Spatial transcriptomic validation using Xenium in situ sequencing confirmed the neuronal diversity identified by single-cell approaches and provided critical anatomical context for the localization and organization of neuronal populations across the dorsal striatum.

Together, these findings define a comprehensive transcriptional framework of striatal neuronal dysfunction in PD, highlighting cell-type– and region-specific vulnerabilities that drive disease progression and providing a foundation for developing targeted strategies to preserve or restore striatal circuit function.