Stochastic misfolding drives the emergence of distinct α-synuclein strains

Raphaella W L So; Benedikt Frieg; José D Camino; Christopher Situ; Mark N Metri; Nicholas R G Silver; Le Yao Li; Alison Mao; Erica Stuart; Gunnar F Schröder; Joel C Watts

doi:10.1016/j.neuron.2026.01.014

Stochastic misfolding drives the emergence of distinct α-synuclein strains

Neuron. 2026 Feb 27:S0896-6273(26)00040-1. doi: 10.1016/j.neuron.2026.01.014. Online ahead of print.

Authors

Affiliations

¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5T 0S8, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
² Ernst Ruska Centre, ER-C-3 Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany.
³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5T 0S8, Canada.
⁴ Ernst Ruska Centre, ER-C-3 Structural Biology, Forschungszentrum Jülich, 52425 Jülich, Germany; Physics Department, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5T 0S8, Canada; Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: joel.watts@utoronto.ca.

PMID: 41763203
DOI: 10.1016/j.neuron.2026.01.014

Abstract

α-Synuclein conformational strains provide a potential explanation for the clinical and pathological differences among synucleinopathies such as Parkinson's disease and multiple system atrophy. However, how distinct α-synuclein strains arise remains unknown. Here, we observed conformational heterogeneity between individual preparations of α-synuclein pre-formed fibrils (PFFs) generated by polymerizing wild-type or A53T-mutant human α-synuclein under identical conditions. Moreover, we found that α-synuclein aggregates formed spontaneously in the brains of a transgenic synucleinopathy mouse model are conformationally diverse. Propagation of stochastically formed PFF- and brain-derived α-synuclein strains in mice initiated several distinct synucleinopathies. The conformational diversity of α-synuclein aggregates across PFF preparations and between individual mice demonstrates that α-synuclein can spontaneously form multiple self-propagating strains within an identical environment. This suggests that stochastic misfolding into distinct aggregate structures drives the emergence of α-synuclein strains and reveals that the intrinsic variability of common synucleinopathy research tools must be considered when designing and interpreting experiments.

Keywords: Parkinson's disease; cryo-electron microscopy; dementia with Lewy bodies; multiple system atrophy; pre-formed fibrils; prion-like propagation; protein aggregation; strain; transgenic mice; α-synuclein.