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

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Abstract

Summary Paragraph Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50–60 and leading to death within a decade 1–3 . It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar alpha-synuclein (aSyn) 4–8 , whose formation shows parallels with prion propagation 9,10 . While fibrils extracted from MSA brains have been structurally characterized 11 , their ability to replicate in a “protein-only” manner has been questioned 12 , and their capacity 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 mice 15 - suggesting direct relevance to MSA - but awaited scrutiny at an 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. Remarkably, the structures of 1B and 1B P are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from MSA patients 11 . 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/1B P that may underlie MSA pathology, offering insights for therapeutic strategies.

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europepmc
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License: CC-BY-NC-ND-4.0