Parkinson’s Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nucleus transcriptome analysis of human post-mortem SNpc obtained from 15 sporadic Parkinson’s Disease (PD) cases and 14 Controls. Our dataset comprises ∼84K nuclei, representing all major cell types of the brain, allowing us to obtain a transcriptome-level characterization of these cell types. Importantly, we identify multiple subpopulations for each cell type and describe specific gene sets that provide insights into the differing roles of these subpopulations. Our findings reveal a significant decrease in neuronal cells in PD samples, accompanied by an increase in glial cells and T cells. Subpopulation analyses demonstrate a significant depletion of tyrosine hydroxylase (TH) enriched astrocyte, microglia and oligodendrocyte populations in PD samples, as well as TH enriched neurons, which are also depleted. Moreover, marker gene analysis of the depleted subpopulations identified 28 overlapping genes, including those associated with dopamine metabolism (e.g., ALDH1A1, SLC6A3 & SLC18A2). Overall, our study provides a valuable resource for understanding the molecular mechanisms involved in dopaminergic neuron degeneration and glial responses in PD, highlighting the existence of novel subpopulations and cell type-specific gene sets.

中文翻译：

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以单细胞分辨率揭示细胞类型对帕金森病的特异性反应

帕金森病 (PD) 是第二常见的神经退行性疾病。PD 的病理特征是多巴胺能神经元的丧失和聚集的 α-突触核蛋白的存在，主要存在于中脑的黑质致密部 (SNpc)。然而，目前尚不清楚不同细胞类型病理学背后的分子机制。在这里，我们展示了从 15 例散发性帕金森病 (PD) 病例和 14 例对照中获得的人类死后 SNpc 的单核转录组分析。我们的数据集包含~84K 细胞核，代表大脑的所有主要细胞类型，使我们能够获得这些细胞类型的转录组水平特征。重要的是，我们确定了每种细胞类型的多个亚群，并描述了特定的基因集，这些基因集提供了对这些亚群的不同作用的见解。我们的研究结果表明，PD 样本中神经元细胞显着减少，同时神经胶质细胞和 T 细胞增加。亚群分析表明，PD 样本中富含酪氨酸羟化酶 (TH) 的星形胶质细胞、小胶质细胞和少突胶质细胞群以及富含 TH 的神经元显着减少。此外，对耗尽亚群的标记基因分析确定了 28 个重叠基因，包括与多巴胺代谢相关的基因（例如 ALDH1A1、SLC6A3 和 SLC18A2）。总体而言，我们的研究为了解 PD 中多巴胺能神经元变性和神经胶质反应所涉及的分子机制提供了宝贵的资源，强调了新亚群和细胞类型特异性基因集的存在。