Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology
Nature. 2025-11-05; :
DOI: 10.1038/s41586-025-09698-1
Lire sur PubMed
https://www.bordeaux-neurocampus.fr/12256
Burger D(#)(1)(2), Kashyrina M(#)(3)(4), van den Heuvel L(#)(1)(2), de La
Seiglière H(3), Lewis AJ(1)(2), De Nuccio F(4), Mohammed I(1)(2)(5), Verchère
J(6), Feuillie C(7), Berbon M(7), Arotcarena ML(3), Retailleau A(3), Bezard
E(3), Canron MH(3), Meissner WG(3)(8), Loquet A(7), Bousset L(9), Poujol C(10),
Nilsson KPR(11), Laferrière F(3), Baron T(6), Lofrumento DD(12), De Giorgi F(3),
Stahlberg H(13)(14), Ichas F(15)(16).
Author information:
(1)Laboratory of Biological Electron Microscopy, Institute of Physics, School of
Basic Science, EPFL, Lausanne, Switzerland.
(2)Department of Fundamental Microbiology, Faculty of Biology and Medicine,
UNIL, Lausanne, Switzerland.
(3)Institut des Maladies Neurodégénératives, UMR 5293, Univ. Bordeaux, CNRS,
Bordeaux, France.
(4)Laboratory of Human Anatomy, Department of Experimental Medicine, Univ.
Salento, Lecce, Italy.
(5)Dubochet Center for Imaging, Lausanne, Genopode (UNIL), EPFL, Lausanne,
Switzerland.
(6)Neurodegenerative Diseases Unit, ANSES, Univ. Lyon, Lyon, France.
(7)Institut de Chimie et Biologie des Membranes et des Nano-objets, UMR 5248,
Univ. Bordeaux, CNRS, Bordeaux INP, Pessac, France.
(8)Service de Neurologie des Maladies Neurodégénératives, IMNc, CHU Bordeaux,
Bordeaux, France.
(9)Laboratoire des Maladies Neurodégénératives, UMR 9199, Univ. Paris-Saclay,
CNRS, CEA, Fontenay-aux-Roses, France.
(10)Bordeaux Imaging Center, UAR 3420, US 4, Univ. Bordeaux, CNRS, INSERM,
Bordeaux, France.
(11)Department of Physics, Chemistry and Biology, Linköping University,
Linköping, Sweden.
(12)Laboratory of Human Anatomy, Department of Biological and Environmental
Sciences and Technologies, Univ. Salento, Lecce, Italy.
(13)Laboratory of Biological Electron Microscopy, Institute of Physics, School
of Basic Science, EPFL, Lausanne, Switzerland. .
(14)Department of Fundamental Microbiology, Faculty of Biology and Medicine,
UNIL, Lausanne, Switzerland. .
(15)Institut des Maladies Neurodégénératives, UMR 5293, Univ. Bordeaux, CNRS,
Bordeaux, France. .
(16)Laboratory of Human Anatomy, Department of Biological and Environmental
Sciences and Technologies, Univ. Salento, Lecce, Italy.
.
(#)Contributed equally
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 decade1-3. It is characterized by glial cytoplasmic inclusions
(GCIs) composed of fibrillar α-synuclein (aSyn)4-8, the formation of which shows
parallels with prion propagation9,10. While fibrils extracted from brains of
individuals with MSA have been structurally characterized11, their ability to
replicate in a protein-only manner has been questioned12, and their ability to
induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain
1B13,14, assembled from recombinant human aSyn, self-replicates in vitro and
induces GCIs in mice15-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 (1BP). We show in vivo that conformational templating enables
fibril strain replication, resulting in MSA-like inclusion pathology. Notably,
the structures of 1B and 1BP are highly similar and mimic the fold of aSyn
observed in one protofilament of fibrils isolated from patients with MSA11.
Moreover, reinjection of crude mouse brain homogenates containing 1BP 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 1BP that may underlie MSA
pathology, offering insights for therapeutic strategies.
© 2025. The Author(s).
DOI: 10.1038/s41586-025-09698-1
PMID: 41193804
Conflict of interest statement: Competing interests: D.B. is an employee of F.
Hoffmann–La Roche. The presented work was conducted before his employment and
had no influence on the design, analysis, interpretation or reporting of the
results of this study. E.B. is a director and shareholder and of Motac
Neuroscience. The other authors declare no competing interests.