1.94 Angstrom structure of synthetic alpha-synuclein fibrils seeding MSA neuropathology

Burger, D.; Kashyrina, M.; Lewis, A. J.; De Nuccio, F.; Mohammed, I.; de La Seigliere, H.; van den Heuvel, L.; Verchere, J.; Feuillie, C.; Berbon, M.; Arotcarena, M.-L.; Retailleau, A.; Bezard, E.; Laferriere, F.; Loquet, A.; Bousset, L.; Baron, T.; Lofrumento, D. D.; De Giorgi, F.; Stahlberg, H.; Ichas, F.

doi:10.1101/2024.07.01.601498

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bioRxiv · 10.1101/2024.07.01.601498

1.94 Angstrom structure of synthetic alpha-synuclein fibrils seeding MSA neuropathology

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Abstract

Summary ParagraphMultiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50-60 and leading to death within a decade1-3. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar alpha-synuclein (aSyn)4-8, whose formation shows parallels with prion propagation9,10. While fibrils extracted from MSA brains have been structurally characterized11, their ability to replicate in a "protein-only" manner has been questioned12, and their capacity 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 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 (1BP). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Remarkably, the structures of 1B and 1BP are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from MSA patients11. 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/1BP that may underlie MSA pathology, offering insights for therapeutic strategies.

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Burger, D., Kashyrina, M., Lewis, A. J., De Nuccio, F., Mohammed, I., de La Seigliere, H., van den Heuvel, L., Verchere, J., Feuillie, C., Berbon, M., Arotcarena, M.-L., Retailleau, A., Bezard, E., Laferriere, F., Loquet, A., Bousset, L., Baron, T., Lofrumento, D. D., De Giorgi, F., Stahlberg, H., Ichas, F.. 2024-07-03. 1.94 Angstrom structure of synthetic alpha-synuclein fibrils seeding MSA neuropathology. https://doi.org/10.1101/2024.07.01.601498

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