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

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.

Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy

“…Intraneuronal inclusions called Lewy bodies and neurites, primarily consisting of αS fibrils, are the major neuropathological hallmark of such diseases [ 2 , 3 ]. However, there is increasing evidence that metastable oligomeric assemblies, formed during the early phases of αS aggregation, play a crucial role in neuronal injury [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Despite their prominent role in the pathogenesis of α-synucleinopathies, the isolation and structural characterization of αS oligomers is extremely difficult because of their instability and transient nature.…”

“…The association of pathogenic αS species with lipid membranes is actually considered to be a primary event in the cascade of neuronal dysfunction in PD [ 8 , 9 , 10 , 11 ]. We have previously described the mechanisms of membrane perturbation and neuronal damage triggered by a range of well-characterized and stable αS aggregates, referred to as type-B* oligomers (OB*), short fibrils (SF), and long fibrils (LF), prepared under physiological conditions, according to developed protocols [ 5 , 7 , 10 ].…”

“…The association of pathogenic αS species with lipid membranes is actually considered to be a primary event in the cascade of neuronal dysfunction in PD [ 8 , 9 , 10 , 11 ]. We have previously described the mechanisms of membrane perturbation and neuronal damage triggered by a range of well-characterized and stable αS aggregates, referred to as type-B* oligomers (OB*), short fibrils (SF), and long fibrils (LF), prepared under physiological conditions, according to developed protocols [ 5 , 7 , 10 ]. OB*, which possess a rudimentary cross-β structure and high solvent-exposed hydrophobicity [ 8 , 10 ], have been previously shown to be harmful to neuronal cells because of their ability to interact aberrantly with neurons and to rapidly penetrate cells [ 8 , 9 , 10 ].…”

“…We have previously described the mechanisms of membrane perturbation and neuronal damage triggered by a range of well-characterized and stable αS aggregates, referred to as type-B* oligomers (OB*), short fibrils (SF), and long fibrils (LF), prepared under physiological conditions, according to developed protocols [ 5 , 7 , 10 ]. OB*, which possess a rudimentary cross-β structure and high solvent-exposed hydrophobicity [ 8 , 10 ], have been previously shown to be harmful to neuronal cells because of their ability to interact aberrantly with neurons and to rapidly penetrate cells [ 8 , 9 , 10 ]. Such oligomers can further aggregate and form fibrils, whose neurotoxicity has been associated with the release of oligomeric-like conformers, that are highly toxic to neuronal cells [ 5 , 7 , 10 ].…”

“…OB*, which possess a rudimentary cross-β structure and high solvent-exposed hydrophobicity [ 8 , 10 ], have been previously shown to be harmful to neuronal cells because of their ability to interact aberrantly with neurons and to rapidly penetrate cells [ 8 , 9 , 10 ]. Such oligomers can further aggregate and form fibrils, whose neurotoxicity has been associated with the release of oligomeric-like conformers, that are highly toxic to neuronal cells [ 5 , 7 , 10 ].…”