The release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells

Roberta Cascella, Serene W. Chen, Alessandra Bigi, José D. Camino, Catherine K. Xu, Christopher M. Dobson, Fabrizio Chiti, Nunilo Cremades () and Cristina Cecchi ()
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Roberta Cascella: University of Florence
Serene W. Chen: Imperial College London
Alessandra Bigi: University of Florence
José D. Camino: Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Unit BIFI-Institute of Physical Chemistry “Rocasolano” (CSIC), University of Zaragoza
Catherine K. Xu: University of Cambridge
Christopher M. Dobson: University of Cambridge
Fabrizio Chiti: University of Florence
Nunilo Cremades: Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Unit BIFI-Institute of Physical Chemistry “Rocasolano” (CSIC), University of Zaragoza
Cristina Cecchi: University of Florence

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract The self-assembly of α-synuclein (αS) into intraneuronal inclusion bodies is a key characteristic of Parkinson’s disease. To define the nature of the species giving rise to neuronal damage, we have investigated the mechanism of action of the main αS populations that have been observed to form progressively during fibril growth. The αS fibrils release soluble prefibrillar oligomeric species with cross-β structure and solvent-exposed hydrophobic clusters. αS prefibrillar oligomers are efficient in crossing and permeabilize neuronal membranes, causing cellular insults. Short fibrils are more neurotoxic than long fibrils due to the higher proportion of fibrillar ends, resulting in a rapid release of oligomers. The kinetics of released αS oligomers match the observed kinetics of toxicity in cellular systems. In addition to previous evidence that αS fibrils can spread in different brain areas, our in vitro results reveal that αS fibrils can also release oligomeric species responsible for an immediate dysfunction of the neurons in the vicinity of these species.

Date: 2021
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DOI: 10.1038/s41467-021-21937-3

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