The spatial landscape of glial pathology and T-cell response in Parkinson's disease substantia nigra [snRNAseq]

Recent evidence, including identification of specific peripheral T-cell receptor sequences, indicates the adaptive immune response is associated with disease pathogenesis. However, the properties of T-cells in the brain regions where neurons degenerate are uncharacterized. We have analyzed the identities and interactions of T-cells in PD in post-mortem brain tissue using single nucleus RNA sequencing, spatial transcriptomics and T-cell receptor sequencing. We found that T-cells in the substantia nigra of PD brain donors exhibit a CD8+ resident memory phenotype, increased clonal expansion, and altered spatial relationships with astrocytes, myeloid cells, and endothelial cells. We also describe regional differences in astrocytic responses to neurodegeneration. Our findings nominate potential molecular and cellular candidates that allow a deeper understanding of the pathophysiology of neurodegeneration in PD. Together, our work represents a major single nucleus and spatial transcriptional resource for the fields of neurodegeneration and PD Overall design: Analysis of human brain samples using snRNAseq, spatial transcriptomics, and TCR sequencing merged with computational techniques to analyze glial pathology and T-call response in PD

近期多项研究证据（包括特定外周T细胞受体（T-cell receptor）序列的鉴定）表明，适应性免疫应答与疾病发病机制存在密切关联。然而，神经元退行性变脑区中的T细胞特性尚未得到系统解析。本研究借助单细胞核RNA测序（single nucleus RNA sequencing, snRNAseq）、空间转录组学及T细胞受体测序技术，对帕金森病（Parkinson's Disease, PD）患者死后脑组织内的T细胞身份特征及相互作用模式展开了分析。研究发现，帕金森病患者脑组织供体的黑质区域内T细胞呈现CD8阳性驻留记忆表型，克隆扩增水平显著升高，且与星形胶质细胞、髓系细胞及内皮细胞的空间分布关系发生改变。本研究同时阐明了星形胶质细胞对神经元退行性变的区域特异性应答差异。本研究结果筛选得到了潜在的分子与细胞候选靶点，可为深入解析帕金森病神经元退行性变的病理生理机制提供支撑。综上，本研究构建了神经元退行性变及帕金森病研究领域内的重要单细胞核与空间转录组学资源库。整体实验设计：通过单细胞核RNA测序、空间转录组学及T细胞受体测序技术分析人脑样本，并结合计算技术解析帕金森病中的胶质细胞病理与T细胞应答反应。