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TitleSynthetic α-synuclein fibrils replicate in mice causing MSA-like pathology.
Journal, issue, pagesNature, Vol. 648, Issue 8093, Page 409-417, Year 2025
Publish dateNov 5, 2025
AuthorsDomenic Burger / Marianna Kashyrina / Lukas van den Heuvel / Hortense de La Seiglière / Amanda J Lewis / Francesco De Nuccio / Inayathulla Mohammed / Jérémy Verchère / Cécile Feuillie / Mélanie Berbon / Marie-Laure Arotcarena / Aude Retailleau / Erwan Bezard / Marie-Hélène Canron / Wassilios G Meissner / Antoine Loquet / Luc Bousset / Christel Poujol / K Peter R Nilsson / Florent Laferrière / Thierry Baron / Dario Domenico Lofrumento / Francesca De Giorgi / Henning Stahlberg / François Ichas /
PubMed AbstractMultiple-system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50-60 years and leading to death within a decade. It is ...Multiple-system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50-60 years and leading to death within a decade. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar α-synuclein (aSyn), the formation of which shows parallels with prion propagation. While fibrils extracted from brains of individuals with MSA have been structurally characterized, their ability to replicate in a protein-only manner has been questioned, and their ability to induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain 1B, assembled from recombinant human aSyn, self-replicates in vitro and induces GCIs in mice-suggesting direct relevance to MSA-but lacks scrutiny at the atomic scale. Here we report high-resolution structural analyses of 1B fibrils and of fibrils extracted from diseased mice injected with 1B that developed GCIs (1B). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Notably, the structures of 1B and 1B are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from patients with MSA. Moreover, reinjection of crude mouse brain homogenates containing 1B into new mice reproduces the same MSA-like pathology induced by the parent synthetic seed 1B. Our findings identify 1B as a synthetic pathogen capable of self-replication in vivo and reveal structural features of 1B and 1B that may underlie MSA pathology, offering insights for therapeutic strategies.
External linksNature / PubMed:41193804 / PubMed Central
MethodsEM (helical sym.)
Resolution1.93 - 3.8 Å
Structure data

19986

9euu

EMDB-19986, PDB-9euu:
Structure of recombinant alpha-synuclein fibrils 1B capable of seeding GCIs in vivo
Method: EM (helical sym.) / Resolution: 1.93 Å

54402

9rzf

EMDB-54402, PDB-9rzf:
Structure of in-vivo formed alpha-synuclein fibrils purified from a M83+/- mouse brain injected with recombinant 1B fibrils
Method: EM (helical sym.) / Resolution: 3.8 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / alpha-synuclein / aSyn / MSA / Prion-like / Fibril / Paired helical filament

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