Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology

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<sup>1-3</sup>. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar α-synuclein (aSyn)<sup>4-8</sup>, the formation of which shows parallels with prion propagation<sup>9,10</sup>. While fibrils extracted from brains of individuals with MSA have been structurally characterized<sup>11</sup>, their ability to replicate in a protein-only manner has been questioned<sup>12</sup>, and their ability to induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain 1B<sup>13,14</sup>, assembled from recombinant human aSyn, self-replicates in vitro and induces GCIs in mice<sup>15</sup>-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<sup>P</sup>). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Notably, the structures of 1B and 1B<sup>P</sup> are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from patients with MSA<sup>11</sup>. Moreover, reinjection of crude mouse brain homogenates containing 1B<sup>P</sup> 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<sup>P</sup> that may underlie MSA pathology, offering insights for therapeutic strategies.

Authors

Institutions

Publication Details

Journal
Nature
Published
2025-11-05
DOI
https://doi.org/10.1038/s41586-025-09698-1
Citations
6
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
8.34
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology

Erwan Bézard, Marie-Laure Arotçarena, Amanda J. Lewis, Antoine Loquet et al.
6 citations
Nature
Parkinson's Disease Mechanisms and Treatments
8.34
article

Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology

Erwan Bézard, Marie-Laure Arotçarena, Amanda J. Lewis, Antoine Loquet, Henning Stahlberg, Inayathulla Mohammed, Marianna Kashyrina, Domenic Burger, Francesca De Giorgi, Christel Poujol, Cécile Feuillie, Dario Domenico Lofrumento, Mélanie Berbon, Aude Retailleau, Marie‐Hélène Canron, Lukas van den Heuvel, Jérémy Verchère, François Ichas, Florent Laferrière, Thierry Baron, Francesco De Nuccio, Luc Bousset, Wassilios G. Meissner, Hortense de La Seiglière, Peter Nilsson
article en
6 citations

Abstract

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<sup>1-3</sup>. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar α-synuclein (aSyn)<sup>4-8</sup>, the formation of which shows parallels with prion propagation<sup>9,10</sup>. While fibrils extracted from brains of individuals with MSA have been structurally characterized<sup>11</sup>, their ability to replicate in a protein-only manner has been questioned<sup>12</sup>, and their ability to induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain 1B<sup>13,14</sup>, assembled from recombinant human aSyn, self-replicates in vitro and induces GCIs in mice<sup>15</sup>-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<sup>P</sup>). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Notably, the structures of 1B and 1B<sup>P</sup> are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from patients with MSA<sup>11</sup>. Moreover, reinjection of crude mouse brain homogenates containing 1B<sup>P</sup> 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<sup>P</sup> that may underlie MSA pathology, offering insights for therapeutic strategies.

NatureVol. 648(8093)
Université Claude Bernard Lyon 1 (FR), Linköping University (SE), Centre National de la Recherche Scientifique (FR), University of Salento (IT), Université de Bordeaux (FR), Inserm (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Institut des Maladies Neurodégénératives (FR), Centre de Recherche en Neurosciences de Lyon (FR), CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR), Bordeaux Population Health (FR), CEA Paris-Saclay (FR), Centre d'Imagerie BioMedicale (CH), Chimie et Biologie des Membranes et des Nanoobjects (FR), Institut Polytechnique de Bordeaux (FR), École Polytechnique Fédérale de Lausanne (CH), University of Lausanne (CH)
Openalex Percentile: Top 2%
Parkinson's Disease Mechanisms and Treatments
8.34
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.