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Article Dans Une Revue Science Advances Année : 2020

Novel self-replicating α-synuclein polymorphs that escape ThT monitoring can spontaneously emerge and acutely spread in neurons

Xuan Yu
Estelle Morvan
Jonathan Daniel
Chuan Qin

Résumé

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

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Neurobiologie
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Dates et versions

hal-03401958 , version 1 (25-10-2021)

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Francesca de Giorgi, Florent Laferrière, Federica Zinghirino, Emilie Faggiani, Alons Lends, et al.. Novel self-replicating α-synuclein polymorphs that escape ThT monitoring can spontaneously emerge and acutely spread in neurons. Science Advances , 2020, 6 (40), pp.eabc4364. ⟨10.1126/sciadv.abc4364⟩. ⟨hal-03401958⟩
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