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.

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, Cristina Cecchi. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - ELETTRONICO. - 12:(2021), pp. 1-16. [10.1038/s41467-021-21937-3]

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

Roberta Cascella
Investigation
;
Alessandra Bigi
Investigation
;
Fabrizio Chiti
Supervision
;
Cristina Cecchi
Supervision
2021

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.
2021
12
1
16
Roberta Cascella, Serene W Chen , Alessandra Bigi, José D Camino, Catherine K Xu, Christopher M Dobson, Fabrizio Chiti, Nunilo Cremades, Cristina Cecchi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1235398
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