Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Department of Neurology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
Sci Adv. 2024 Jan 12;10(2):eadi8287. doi: 10.1126/sciadv.adi8287. Epub 2024 Jan 10.
Parkinson's disease (PD) is characterized pathologically by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Whether cell types beyond DA neurons in the SN show vulnerability in PD remains unclear. Through transcriptomic profiling of 315,867 high-quality single nuclei in the SN from individuals with and without PD, we identified cell clusters representing various neuron types, glia, endothelial cells, pericytes, fibroblasts, and T cells and investigated cell type-dependent alterations in gene expression in PD. Notably, a unique neuron cluster marked by the expression of , a PD risk gene, also displayed vulnerability in PD. We validated -enriched neurons in midbrain organoids and the mouse SN. Our results demonstrated distinct transcriptomic signatures of the -enriched neurons in the human SN and implicated reduced RIT2 expression in the pathogenesis of PD. Our study sheds light on the diversity of cell types, including DA neurons, in the SN and the complexity of molecular and cellular changes associated with PD pathogenesis.
帕金森病（PD）的特征是黑质（SN）中的多巴胺能（DA）神经元丧失。SN 中除 DA 神经元以外的细胞类型是否易患 PD 尚不清楚。通过对来自有无 PD 个体的 315867 个高质量 SN 单细胞的转录组分析，我们鉴定了代表各种神经元类型、神经胶质细胞、内皮细胞、周细胞、成纤维细胞和 T 细胞的细胞簇，并研究了 PD 中与细胞类型相关的基因表达改变。值得注意的是，一个由 PD 风险基因 表达标记的独特神经元簇在 PD 中也表现出易感性。我们在中脑类器官和小鼠 SN 中验证了富含 的神经元。我们的结果表明，人类 SN 中富含 的神经元具有独特的转录组特征，并提示 RIT2 表达减少与 PD 发病机制有关。我们的研究揭示了 SN 中包括 DA 神经元在内的多种细胞类型的多样性，以及与 PD 发病机制相关的分子和细胞变化的复杂性。
