9K23

Cryo-EM structure of alpha-synuclein Mini S fibril

Summary for 9K23

• Entry DOI: 10.2210/pdb9k23/pdb
• EMDB information: 61988
• Descriptor: Alpha-synuclein (1 entity in total)
• Functional Keywords: protein fibril, amyloid
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 6
• Total formula weight: 87007.11

Authors

Xia, W.C.,Liu, C. (deposition date: 2024-10-17, release date: 2025-04-23)

Primary citation

Han, Y.,Li, J.,Xia, W.,Li, Q.,Sun, Z.,Zeng, W.,Hu, Y.,Luk, K.C.,Liu, C.,Xiang, S.,He, Z.
Fibril fuzzy coat is important for alpha-synuclein pathological transmission activity.
Neuron, 2025

PubMed Abstract: α-synuclein transmission and propagation are hallmarks of synucleinopathies, yet the molecular mechanisms remain elusive. Using α-synuclein preformed fibrils as pathological seeds, we observed a gradual decline in neuronal transmission activity during serial propagation. Fibril polymorphisms were identified from the initial generation: mini-P, with higher neuronal seeding activity, and mini-S, which accelerated recombinant α-synuclein aggregation. Changes in their proportions during propagation explained the overall decline in transmission activity. Cryoelectron microscopy and solid-state nuclear magnetic resonance revealed that both fibrils shared similar core regions but differed in their fuzzy coat flexibilities. The interaction between the fuzzy coat and fibril core substantially influenced neuronal transmission, a model further supported by hydrogen/deuterium exchange mass spectrometry. A mini-P-selective antibody identified active fibril types in newly propagated brain regions in human synucleinopathies. This study highlights the fuzzy coat's pivotal role in pathological protein transmission and suggests it as a potential therapeutic target for synucleinopathies.

PubMed: 40215967
DOI: 10.1016/j.neuron.2025.03.019

Experimental method

ELECTRON MICROSCOPY (2.6 Å)