Glial multicellular programs reveal distinct patient stratification in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration. While the role of glial cells in PD is increasingly recognized, the coordinated multicellular responses driving PD within the dorsal striatum remain poorly understood. By integrating single-nucleus RNA sequencing of 56 donors with targeted spatial transcriptomics, we disentangle regional from PD-related molecular programs across astrocytes, microglia and oligodendroglia. We identify PD-associated glial subpopulations organized into two distinct multicellular programs: one inflammatory and one UPR-associated, where each patient is dominated by one of these programs. Notably, these programs partition the molecular changes typically associated with PD into two specific, non-overlapping signatures. Multi-region analysis revealed these signatures are globally enriched across the sampled areas and Lewy body disease stages, from brainstem-predominant to neocortical, demonstrating that PD is characterized by mutually exclusive, brain-wide glial multicellular states. Our findings redefine glial alterations in PD as systemic and multicellular, providing a framework for patient stratification and the development of targeted, state-specific therapeutic interventions.