9OBP

Cryo-EM structure of alpha-synuclein filaments derived from the frontal cortex of the case of atypical multiple system atrophy

Summary for 9OBP

• Entry DOI: 10.2210/pdb9obp/pdb
• Related: 9E9X
• EMDB information: 70295
• Descriptor: Alpha-synuclein, Unidentified protein (2 entities in total)
• Functional Keywords: homo-dimer, asymmetric, filaments, multiple system atrophy, lewy body dementia, protein fibril
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 15
• Total formula weight: 146978.78

Authors

Enomoto, M.,Martinez-Valbuena, I.,Forrest, S.L.,Xu, X.,Munhoz, R.,Li, J.,Rogaeva, E.,Lang, A.E.,Kovacs, G.G. (deposition date: 2025-04-23, release date: 2025-06-25, Last modification date: 2025-07-02)

Primary citation

Enomoto, M.,Martinez-Valbuena, I.,Forrest, S.L.,Xu, X.,Munhoz, R.P.,Li, J.,Rogaeva, E.,Lang, A.E.,Kovacs, G.G.
Lewy-MSA hybrid fold drives distinct neuronal alpha-synuclein pathology.
Commun Biol, 8:929-929, 2025

PubMed Abstract: The ordered assembly of α-synuclein protein encoded by SNCA into filaments characterizes neurodegenerative synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal and multiple system atrophy (MSA), predominantly oligodendrocytic α-synuclein pathology affecting subcortical brain structures. Based on cryo-electron microscopy, it was reported that the structures of α-synuclein filaments from LBD differ from MSA and juvenile-onset synucleinopathy (JOS). The rare atypical MSA subtype shows abundant neuronal argyrophilic α-synuclein inclusions in the limbic system. Current concepts indicate that disease entities are characterized by unique protofilament folds. Here we demonstrate that α-synuclein can form a Lewy-MSA hybrid fold, leading to the atypical histopathological form of MSA. Distinct biochemical characteristics of α-synuclein, as demonstrated by protease-sensitivity digestion assay, seed amplification assays (SAAs), and conformational stability assays (CSA), are also linked to cytopathological differences. We expand the current structure-based classification of α-synucleinopathies and propose that cell-specific protein pathologies can be associated with distinct filament folds.

PubMed: 40523906
DOI: 10.1038/s42003-025-08355-7

Experimental method

ELECTRON MICROSCOPY (2.5 Å)