The spatial landscape of glial pathology and T cell response in Parkinson’s disease substantia nigra

Maxwell Ma, Fahad Paryani, Kelly Jakubiak, Shengnan Xia, Susumu Antoku, Adithya Kannan, Jaeseung Lee, Nacoya Madden, Shailesh Senthil Kumar, Juncheng Li, David Chen, Gunnar Hargus, Aayushi Mahajan, Xena Flowers, Ashley S. Harms, David Sulzer, James E. Goldman, Peter A. Sims and Osama Al-Dalahmah ()
Additional contact information
Maxwell Ma: Columbia University Irving Medical Center
Fahad Paryani: Columbia University Irving Medical Center
Kelly Jakubiak: Columbia University Irving Medical Center
Shengnan Xia: Columbia University Irving Medical Center
Susumu Antoku: Columbia University Irving Medical Center
Adithya Kannan: Columbia University Irving Medical Center
Jaeseung Lee: Columbia University Irving Medical Center
Nacoya Madden: Columbia University Irving Medical Center
Shailesh Senthil Kumar: Columbia University Irving Medical Center
Juncheng Li: Columbia University Irving Medical Center
David Chen: Columbia University Irving Medical Center
Gunnar Hargus: Columbia University Irving Medical Center
Aayushi Mahajan: Columbia University Irving Medical Center
Xena Flowers: Columbia University Irving Medical Center
Ashley S. Harms: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
David Sulzer: Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
James E. Goldman: Columbia University Irving Medical Center
Peter A. Sims: Columbia University Irving Medical Center
Osama Al-Dalahmah: Columbia University Irving Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: Abstract Parkinson’s Disease (PD) is an incurable neurodegenerative disease that causes movement disorders. Neurons in PD aggregate α-synuclein and are depleted from the substantia nigra (SN), which is a movement control hub. The presence of α-synuclein-reactive T cells in PD patient blood suggests a role for adaptive immunity in the pathogenesis of PD. However, the characteristics of this response within the brain are not well understood. Here, we employed single-nucleus RNAseq, spatial transcriptomics, and T cell receptor (TCR) sequencing to analyze T cell and glial cell states in post-mortem PD brain tissue. CD8 + T cells were enriched in the PD SN and characterized by clonal expansion and TCR sequences with homology to those reactive to α-synuclein. Furthermore, PD T cells were spatially correlated with CD44+ astrocytes, which increased in the PD SN. Silencing CD44 in cultured astrocytes attenuated neuroinflammatory signatures, suggesting a potential therapeutic target. These findings provide insight into the neurodegenerative niche underlying T cell-mediated neuroinflammation in PD.

Date: 2025
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DOI: 10.1038/s41467-025-62478-3

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