Spatial transcriptomics identifies novel markers of vulnerable and resistant dopamine neurons

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understand their differential vulnerability in Parkinson Disease. However, reported transcriptional profiles for these neuron populations rely on studies in rodents and display extensive variability across small sample sizes. Here, we use laser capture microdissection coupled with RNA sequencing to analyze individually isolated SNc and VTA dopamine neurons in a large human dataset. By applying an iterative random pooling strategy as input to DESeq2, we describe a minimal cohort size that identifies 33 stably differentially expressed dopamine population-specific markers. Among these, we identify three transcripts, ZCCHC12, CDH13 and SERPINE2, that together faithfully classify SNc or VTA dopamine neurons in both human and mouse. These novel markers will be vital for future studies aiming to distinguish the identity of stem cell-derived dopamine neurons or to induce dopamine neuron resilience.