9RB9

Wild-type alpha-synuclein fibril - Type 3-2

Summary for 9RB9

• Entry DOI: 10.2210/pdb9rb9/pdb
• Related: 9rb3
• EMDB information: 53888
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: alpha-synuclein, fibril, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 10
• Total formula weight: 144761.08

Authors

So, R.W.L.,Frieg, B.,Schroeder, G.F.,Watts, J.C. (deposition date: 2025-05-21, release date: 2026-03-11)

Primary citation

So, R.W.L.,Frieg, B.,Camino, J.D.,Situ, C.,Metri, M.N.,Silver, N.R.G.,Li, L.Y.,Mao, A.,Stuart, E.,Schroder, G.F.,Watts, J.C.
Stochastic misfolding drives the emergence of distinct alpha-synuclein strains.
Neuron, 2026

PubMed 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.

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

Experimental method

ELECTRON MICROSCOPY (3.04 Å)