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, S. KUMAR, Juncheng Li, David Chen, Gunnar Hargus, Aayushi Mahajan, Xena Flowers, Ashley S. Harms, David Sulzer, James E. Goldman, Peter A. Sims, Osama Al‐Dalahmah
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. Neuroinflammation is understudied in Parkinson’s disease (PD). Ma et al. found that clonally expanded CD8 + T cells accumulate in the brains of PD patients and interact with specific astrocytic support cells, which may fuel harmful neuroinflammation.