Why Some Neurons Die First: Uncovering the Regulatory Programs of Selective Neuronal Vulnerability

Synucleinopathies are a group of disorders, including Parkinson's disease, characterized by the formation of α-synuclein (αSyn) aggregates and neurodegeneration in specific brain regions. However, the molecular mechanisms underlying the differential neuronal susceptibility, known as selective vulnerability, remain poorly understood. To investigate these mechanisms, we used a mouse model of synucleinopathy that drives pathogenic αSyn overexpression in neuronal populations of the substantia nigra and locus coeruleus, two regions that exhibit distinct temporal patterns of vulnerability. Single-nucleus RNA sequencing, combined with a gene regulatory network reconstructed from public datasets, recovered associations between neuronal vulnerability and gene expression regulators with established roles in neurodegeneration, as well as newly identified candidates not previously linked to this process. In particular, we uncovered a set of 26 regulators that displayed changes in activity in both dopaminergic and noradrenergic neurons that closely paralleled their distinct neurodegeneration kinetics. Neurodegeneration-associated changes in the activity of this set of regulators were further validated using data from human cells and Parkinson's disease patients. Finally, we show evidence suggesting that intrinsic differences in the basal expression of neuroprotective regulatory genes may contribute to the differential responses of these neuronal populations to αSyn pathology.