Glial multicellular programs reveal distinct patient stratification in Parkinson's disease.
Glial multicellular programs reveal distinct patient stratification in Parkinson's disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
ES · Author affiliation · country only
Unit of Cell Biology, Department of Neuroscience, Institute for Biomedical Research and Innovation of Cádiz (INiBICA), University of Cádiz, Cádiz, Spain.Location evidence
Munich, DE · Author affiliation
Institute of Computational Biology, Helmholtz Center, Munich, Germany.Location evidence
Stockholm, SE · Author affiliation
Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.Location evidence
Uppsala, SE · Author affiliation
Department of Information Technology, Uppsala University, Uppsala, Sweden.Location evidence
Boston, US · Author affiliation
Department of Neurology, Massachusetts General Hospital, Boston Massachusetts, USA.Location evidence
Madrid, ES · Author affiliation
Ciber de Salud Mental (CIBERSAM), ISCIII, Madrid, 28029 Madrid, Spain.Location evidence
Publication status: preprint
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Original abstract
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.