Novel self-replicating α-synuclein polymorphs that escape ThT monitoring can spontaneously emerge and acutely spread in neurons
Francesca De Giorgi, Florent Laferrière, Federica Zinghirino, Emilie Faggiani, Alons Lends, Mathilde Bertoni, Xuan Yu, Axelle Grélard, Estelle Morvan, Birgit Habenstein, Nathalie Dutheil, Évelyne Doudnikoff, Jonathan Daniel, Stéphane Claverol, Chuan Qin, Antoine Loquet, Erwan Bézard, François Ichas
Abstract
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.