PQG Working Group

Tushar Kamath

PhD Candidate, Biophysics, Broad Institute
MD Student, Harvard Medical School

Vulnerabilities of midbrain dopaminergic neurons to Parkinson’s disease revealed by single-cell genomics

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 DA neuron types in the SNpc and their relative vulnerabilities to PD, we developed a protocol to enrich and transcriptionally profile thousands of midbrain DA neurons from PD patients and matched controls. We identified 10 populations and spatially localized each within the SNpc using Slide-seq, a high-resolution spatial transcriptomics technology. 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, relative to other DA types, 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 sporadic PD. These analyses highlight the importance of cell-intrinsic pathways in determining the differential vulnerability of DA neurons to degeneration in PD.