AAIC 2021 | Risk genes linked to dopaminergic neuron vulnerability in Parkinson’s

Evan Macosko, MD, PhD, Broad Institute of MIT and Harvard, Cambridge, MA, outlines the work his lab has conducted on characterizing midbrain dopaminergic neurons at single-cell resolution. Midbrain dopaminergic neuron loss and the consequential motor symptoms are characteristic of Parkinson’s disease. However, within the substantia nigra, one area notably affected in Parkinson’s disease, some cells are more impacted than others. To understand which cells are preferentially affected, an analysis of over 16,000 dopaminergic neurons was conducted using post-mortem samples from patients with Parkinson’s and controls. Detailed transcriptomic profiling at a single cell level identified 10 subpopulations of dopaminergic neurons, broadly categorized into SOX6-positive and CALB1-positive. When assessed in the context of disease, it was demonstrated that several of the CALB1 populations were preferentially resistant, while the SOX6_AGTR1 population was highly depleted. Genetic analysis revealed that there was a statistically significant enrichment of common gene variants associated with Parkinson’s in the SOX6_AGTR1 population. This interview took place during the Alzheimer’s Association International Conference (AAIC) 2021.