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.

doi:10.1101/2025.08.19.670819

bioRxiv · 10.1101/2025.08.19.670819

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.

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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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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.. 2025-08-23. α-Synuclein driven cell susceptibility in Parkinson's disease. https://doi.org/10.1101/2025.08.19.670819

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