See the accompanying single nuclei data at


Abstract: The loss of some dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson’s Disease (PD). Yet, the molecular features associated with DA neuron vulnerability have not yet been fully identified. To comprehensively characterize nigral DA neuron types and their relative vulnerabilities to PD, we developed a protocol to enrich and transcriptionally profile thousands of DA neurons from PD patients and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified 10 populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss and showed the strongest upregulation of targets of TP53 and NR2F2, nominating molecular processes associated with degeneration in vivo. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic pathways in determining the differential vulnerability of DA neurons to PD-associated degeneration.