LCM-seq identifies robust markers of vulnerable and resistant human midbrain dopamine neurons

Abstract

ABSTRACTDefining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons in human is critical to understanding their differential vulnerability in Parkinson Disease. However, reported marker profiles for these neuron populations are derived predominantly from rodents, utilize small sample sizes and display extensive variability between studies. Here, we map selective expression profiles of dopamine neurons in an extensive collection of human SNc and VTA using laser capture microdissection coupled with Smart-seq2 RNA sequencing (LCM-seq). By applying a bootstrapping strategy as sample input to DESeq2, we identify 33 differentially expressed SNc- or VTA-specific markers and we also compute the minimal cohort size required to identify differentially expressed genes (DEGs) that are concordant regardless of cohort size. Among the identified DEGs, ZCCHC12, CDH13 and SERPINE2, are minimally required to distinguish SNc or VTA dopamine neurons in both human and mouse. In summary, our study identifies novel markers, besides previously identified ones, which will be instrumentsal for future studies aiming to modulate dopamine neuron resilience as well as validate cell identity of stem cell-derived dopamine neurons.