Single-cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging, and disease

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. [Display omitted] •Single-cell spatial transcriptomic study of mouse brain expression in health, age, and disease•Deep characterization of dopaminergic expression using Stereo-seq and TRAP•SpatialBrain: resource for expression data exploration Kilfeather et al. showcase a single-cell spatial transcriptomic study of mouse brain spanning 29 cell types. They describe gene expression changes in health, age, and a model of Parkinson’s disease. Using TRAP, they further interrogate dopaminergic expression and demonstrate a role for CASR in modulating calcium handling.