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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月4日

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  • 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,
  • Osama Al-Dalahmah

摘要

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.