Parkinson’s disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer’s disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.

中文翻译：

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帕金森病大脑的单细胞转录组学和蛋白质组学分析


帕金森病 （PD） 是一种普遍存在的神经退行性疾病，最近的证据表明，发病机制可能部分由炎症过程介导，其分子和细胞结构在很大程度上是未知的。为了识别和表征 PD 中选择性脆弱的脑细胞群，我们进行了单核转录组学和无偏倚蛋白质组学，以分析 6 名晚期 PD 个体和 6 名年龄匹配的对照者的死后人脑前额叶皮层。对近 80,000 个细胞核的分析导致鉴定出八种主要脑细胞类型，包括 PD 中脑驻留 T 细胞升高，每种细胞都有不同的转录变化，与已知的 PD 遗传学一致。通过分析死后相同脑组织中的路易体病理学，我们发现 α-突触核蛋白病理学与兴奋性神经元中的伴侣表达呈负相关。检查细胞间相互作用，我们发现神经元-星形胶质细胞相互作用选择性减弱，神经炎症增强。对相同大脑的蛋白质组学分析确定了前额叶皮层中的突触蛋白，这些蛋白在 PD 中优先下调。通过将这个单细胞 PD 数据集与已发表的阿尔茨海默病 （AD） 中相似大脑区域的分析进行比较，我们在神经元中没有发现常见的差异表达基因，但在神经胶质细胞中发现了许多共享的差异表达基因，这表明 PD 和 AD 的疾病病因，尤其是在神经元脆弱性的情况下，可能是不同的。