α-Synuclein driven cell susceptibility in Parkinson’s disease

Early cellular events in Parkinson’s disease (PD) remain elusive. While aggregation of α-synuclein (αSyn) into Lewy bodies marks advanced pathology, smaller αSyn oligomers have been implicated in prodromal stages. Here we map αSyn oligomers at single-particle resolution in post-mortem brain tissue from Braak stage 3/4 PD cases and matched controls. Quantitative imaging of 9,882 neurons across four regions captured over 112 million αSyn oligomers. Mean intracellular α-Syn burden was unchanged between groups, but PD samples contained a higher fraction of neurons whose oligomer load exceeded a specific aggregation threshold. We term these aggregation-susceptible cells (ASCs). ASC enrichment in vulnerable regions supports a population-level model in which early pathology arises from a stochastic shift in cellular composition rather than altered αSyn aggregation kinetics. This human-tissue, large-scale dataset provides a quantitative framework for detecting ASCs and for testing population-level interventions in PD and related proteinopathies.