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TitleLewy-MSA hybrid fold drives distinct neuronal α-synuclein pathology.
Journal, issue, pagesCommun Biol, Vol. 8, Issue 1, Page 929, Year 2025
Publish dateJun 16, 2025
AuthorsMasahiro Enomoto / Ivan Martinez-Valbuena / Shelley L Forrest / Xiaoxiao Xu / Renato P Munhoz / Jun Li / Ekaterina Rogaeva / Anthony E Lang / Gabor G Kovacs /
PubMed AbstractThe ordered assembly of α-synuclein protein encoded by SNCA into filaments characterizes neurodegenerative synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal and multiple system ...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.
External linksCommun Biol / PubMed:40523906 / PubMed Central
MethodsEM (helical sym.)
Resolution2.5 - 3.2 Å
Structure data

47820

9e9x

EMDB-47820, PDB-9e9x:
Cryo-EM structure of alpha-synuclein filaments derived from the temporal cortex of the case of atypical multiple system atrophy
Method: EM (helical sym.) / Resolution: 3.2 Å

70295

9obp

EMDB-70295, PDB-9obp:
Cryo-EM structure of alpha-synuclein filaments derived from the frontal cortex of the case of atypical multiple system atrophy
Method: EM (helical sym.) / Resolution: 2.5 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / homo-dimer / asymmetric / filaments / multiple system atrophy / Lewy body dementia

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