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

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^1-3. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar α-synuclein (aSyn)^4-8, the formation of which shows parallels with prion propagation^9,10. 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 1B^13,14, 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 (1B^P). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Notably, the structures of 1B and 1B^P 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 1B^P 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^P that may underlie MSA pathology, offering insights for therapeutic strategies.