Emergence of stealth polymorphs that escape α-synuclein amyloid monitoring, take over and acutely spread in neurons

De Giorgi, F.; Laferriere, F.; Zinghirino, F.; Faggiani, E.; Lends, A.; Bertoni, M.; Yu, X.; Grelard, A.; Morvan, E.; Habenstein, B.; Dutheil, N.; Doudnikoff, E.; Daniel, J.; Claverol, S.; Qin, C.; Loquet, A.; Bezard, E.; Ichas, F.

doi:10.1101/2020.02.11.943670

bioRxiv · 10.1101/2020.02.11.943670

Emergence of stealth polymorphs that escape α-synuclein amyloid monitoring, take over and acutely spread in neurons

De Giorgi, F.·Laferriere, F.·Zinghirino, F.·Faggiani, E.·Lends, A.·Bertoni, M.·Yu, X.·Grelard, A.·Morvan, E.·Habenstein, B.·Dutheil, N.·Doudnikoff, E.·Daniel, J.·Claverol, S.·Qin, C.·Loquet, A.·Bezard, E.·Ichas, F.

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Abstract

The conformational strain diversity characterizing -synuclein (-syn) amyloid fibrils is possibly at the origin of the different clinical presentations of synucleinopathies. Experimentally, various -syn fibril polymorphs have been obtained from distinct fibrillization conditions by altering the medium constituents and were selected by amyloid monitoring using the probe Thioflavin T (ThT). We report here that besides classical ThT positive products, fibrillization in saline simultaneously gives rise to competing fibril polymorphs that are invisible to ThT (stealth polymorphs), and that can take over. Due to competition, spontaneous generation of such stealth polymorphs bears on the apparent fibrillization kinetics and on the final plateau values. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. Compared to their ThT-positive counterparts, and as judged from their chemical shift resonances fingerprint, these new stealth polymorphs present a yet undescribed atomic organization and show an exacerbated propensity (approx. 20-fold) towards self-replication in cortical neurons. They also trigger a long distance synucleinopathic spread along nigro-striatal projections in vivo. In order to rapidly screen fibrillization products for the presence of such stealth polymorphs, we designed a simple multiplexed assay that can be easily and rapidly operated. This assay allows us to demonstrate the sustainability of the conformational replication of these novel and particularly invasive strains. It should also be of help to avoid erroneous upstream interpretations of fibrillization rates based on sole ThT, and to expedite further structural and functional characterization of stealth amyloid assemblies. One Sentence Summarystealth -synuclein fibrils take over

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De Giorgi, F., Laferriere, F., Zinghirino, F., Faggiani, E., Lends, A., Bertoni, M., Yu, X., Grelard, A., Morvan, E., Habenstein, B., Dutheil, N., Doudnikoff, E., Daniel, J., Claverol, S., Qin, C., Loquet, A., Bezard, E., Ichas, F.. 2020-02-12. Emergence of stealth polymorphs that escape α-synuclein amyloid monitoring, take over and acutely spread in neurons. https://doi.org/10.1101/2020.02.11.943670

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