The brain is spatially organized and contains unique cell types, each performing diverse functions and exhibiting differential susceptibility to neurodegeneration. This is exemplified in Parkinson’s disease with the preferential loss of dopaminergic neurons of the substantia nigra pars compacta. Using a Parkinson’s transgenic model, we conducted a single-cell spatial transcriptomic and dopaminergic neuron translatomic analysis of young and old mouse brains. Through the high resolving capacity of single-cell spatial transcriptomics, we provide a deep characterization of the expression features of dopaminergic neurons and 27 other cell types within their spatial context, identifying markers of healthy and aging cells, spanning Parkinson’s relevant pathways. We integrate gene enrichment and genome-wide association study data to prioritize putative causative genes for disease investigation, identifying CASR as a regulator of dopaminergic calcium handling. These datasets represent the largest public resource for the investigation of spatial gene expression in brain cells in health, aging, and disease.

中文翻译：

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健康、衰老和疾病中多巴胺能神经元的单细胞空间转录组学和跨原子分析


大脑在空间上是有组织的，包含独特的细胞类型，每种细胞类型都执行不同的功能，并表现出对神经退行性变的不同敏感性。这在帕金森病中表现为黑质致密部多巴胺能神经元优先丢失。使用帕金森病转基因模型，我们对年轻和老年小鼠大脑进行了单细胞空间转录组学和多巴胺能神经元跨耳瘤分析。通过单细胞空间转录组学的高分辨率能力，我们提供了多巴胺能神经元和其他 27 种细胞类型在其空间背景下的表达特征的深入表征，识别健康和衰老细胞的标志物，跨越帕金森病的相关通路。我们整合了基因富集和全基因组关联研究数据，以优先考虑用于疾病调查的推定致病基因，将 CASR 确定为多巴胺能钙处理的调节因子。这些数据集代表了研究健康、衰老和疾病中脑细胞空间基因表达的最大公共资源。