%0 Journal Article
%T Novel self-replicating α-synuclein polymorphs that escape ThT monitoring can spontaneously emerge and acutely spread in neurons
%V 6
%N 40
%P eabc4364
%U https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abc4364
%X The conformational strain diversity characterizing α-synuclein (α-syn) amyloid fibrils is thought to determine the different clinical presentations of neurodegenerative diseases underpinned by a synucleinopathy. Experimentally, various α-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 that, concurrent with classical ThT-positive products, fibrillization in saline also gives rise to polymorphs invisible to ThT (τ
              −
              ). The generation of τ
              −
              fibril polymorphs is stochastic and can skew the apparent fibrillization kinetics revealed by ThT. Their emergence has thus been ignored so far or mistaken for fibrillization inhibitions/failures. They present a yet undescribed atomic organization and show an exacerbated propensity toward self-replication in cortical neurons, and in living mice, their injection into the substantia nigra pars compacta triggers a synucleinopathy that spreads toward the dorsal striatum, the nucleus accumbens, and the insular cortex.
%G en
%J Science Advances
%A De Giorgi, Francesca
%A Laferrière, Florent
%A Zinghirino, Federica
%A Faggiani, Emilie
%A Lends, Alons
%A Bertoni, Mathilde
%A Yu, Xuan
%A Grélard, Axelle
%A Morvan, Estelle
%A Habenstein, Birgit
%A Dutheil, Nathalie
%A Doudnikoff, Evelyne
%A Daniel, Jonathan
%A Claverol, Stéphane
%A Qin, Chuan
%A Loquet, Antoine
%A Bezard, Erwan
%A Ichas, François
%D 10/2020
%K highlight
peer-reviewed