Early α-synuclein aggregation is overall delayed and it can occur by a stepwise mechanism

It is well-known that α-synuclein (Syn) protein aggregation is implicated in the pathogenesis of Parkinson's disease. There is an increased evidence that large protein aggregates populate very early the subsaturated solutions of several aggregate-prone proteins, including Syn. The role of these...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2022-12, Vol.635, p.30-36
Main Authors: Saraiva, Marco A., Florêncio, M. Helena
Format: Article
Language:English
Subjects:
alpha-Synuclein - metabolism
Amyloid - metabolism
Amyloidogenic Proteins
Early aggregation
Humans
Parkinson Disease - metabolism
Primary nucleation pathway
Protein Aggregates
Stopped-flow
α-synuclein
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Summary:It is well-known that α-synuclein (Syn) protein aggregation is implicated in the pathogenesis of Parkinson's disease. There is an increased evidence that large protein aggregates populate very early the subsaturated solutions of several aggregate-prone proteins, including Syn. The role of these early large protein aggregates and the reaction processes that they involve remain elusive. Amyloid protein's fluorophores (aromatic residues) can retrieve information regarding the amyloid protein's aggregation, by monitoring their fluorescence intensity. By excitation of Syn tyrosine residues in a low ionic strength medium (0.01 M tris-HCl) and collecting the time resolved fluorescence (stopped-flow analysis) it was possible to discriminate a time window of the first ca. 2 s, corresponding to the prevalent dissociation of early large Syn aggregates formed. Lowering even further the media ionic strength, such as Syn in water and Syn in solution containing 1,4-dioxane (pH ≈ 6.5), the above referred time window of the first ca. 2 s was abolished. It should be expected that Syn aggregation mainly occurred. In fact, Syn aggregation is initially delayed by the addition of a structure-induced agent (1,4-dioxane) in a stepwise mechanism. This study retrieves that very early the large Syn aggregates formed are unstructured and, in low ionic strength media (>0.01 M), they restructure in the dissociation process and intertwined the occurrence of its aggregation. In lower ionic strength media (
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2022.10.028