α-Synuclein driven cell susceptibility in Parkinson's disease
Breiter, J. C.; Beckwith, J. S.; Brock, E. E.; Lachica, J.; Toomey, C. E.; Fu, B.; Ryten, M.; Weiss, L. E.; Wood, N. W.; Gandhi, S.; Vendruscolo, M.; Lee, S. F.
Show abstract
Early cellular events in Parkinsons disease (PD) remain elusive. While aggregation of -synuclein (Syn) into Lewy bodies marks advanced pathology, smaller Syn oligomers have been implicated in prodromal stages. Here we map Syn 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 Syn oligomers. Mean intracellular -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 Syn 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.
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