The spatial landscape of glial pathology and T cell response in Parkinson’s disease substantia nigra
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.
Authors
- David Chen (ORCID: https://orcid.org/0000-0002-9710-1857)
- S. KUMAR (ORCID: https://orcid.org/0009-0002-2653-5946)
- Gunnar Hargus (ORCID: https://orcid.org/0000-0001-6487-8857)
- James E. Goldman (ORCID: https://orcid.org/0000-0003-2135-8936)
- Xena Flowers
- David Sulzer (ORCID: https://orcid.org/0000-0001-7632-0439)
- Adithya Kannan (ORCID: https://orcid.org/0000-0001-7359-184X)
- Fahad Paryani (ORCID: https://orcid.org/0000-0003-1418-1386)
- Jaeseung Lee (ORCID: https://orcid.org/0009-0003-0806-093X)
- Ashley S. Harms (ORCID: https://orcid.org/0000-0002-7054-2812)
- Maxwell Ma
- Aayushi Mahajan (ORCID: https://orcid.org/0000-0003-3966-2936)
- Susumu Antoku (ORCID: https://orcid.org/0000-0002-0698-6224)
- Peter A. Sims (ORCID: https://orcid.org/0000-0002-3921-4837)
- Osama Al‐Dalahmah (ORCID: https://orcid.org/0000-0002-3442-5459)
- Nacoya Madden
- Kelly Jakubiak (ORCID: https://orcid.org/0009-0002-6932-4460)
- Juncheng Li (ORCID: https://orcid.org/0009-0008-0934-1027)
- Shengnan Xia (ORCID: https://orcid.org/0009-0001-3728-6669)
Institutions
- Bank of America (US)
- Bank Street College of Education (US)
- Columbia University Irving Medical Center (US)
- University of Alabama at Birmingham (US)
- New York Psychoanalytic Society and Institute (US)
- Research Network (United States) (US)
- Neurological Surgery (US)
- New York State Psychiatric Institute
- Columbia University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-04
- DOI
- https://doi.org/10.1038/s41467-025-62478-3
- Citations
- 13
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 10.11
Funders
- Michael J. Fox Foundation for Parkinson's Research