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The Pathological G51D Mutation in Alpha-Synuclein Oligomers Confers Distinct Structural Attributes and Cellular Toxicity.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Xu, Catherine K 
Castellana-Cruz, Marta 
Chen, Serene W 
Du, Zhen 

Abstract

A wide variety of oligomeric structures are formed during the aggregation of proteins associated with neurodegenerative diseases. Such soluble oligomers are believed to be key toxic species in the related disorders; therefore, identification of the structural determinants of toxicity is of upmost importance. Here, we analysed toxic oligomers of α-synuclein and its pathological variants in order to identify structural features that could be related to toxicity and found a novel structural polymorphism within G51D oligomers. These G51D oligomers can adopt a variety of β-sheet-rich structures with differing degrees of α-helical content, and the helical structural content of these oligomers correlates with the level of induced cellular dysfunction in SH-SY5Y cells. This structure-function relationship observed in α-synuclein oligomers thus presents the α-helical structure as another potential structural determinant that may be linked with cellular toxicity in amyloid-related proteins.

Description

Keywords

Parkinson’s disease, familial mutations, toxic oligomers, α-helical structure, α-synuclein, Humans, Mutation, Neurodegenerative Diseases, Protein Aggregates, Protein Aggregation, Pathological, Protein Binding, Protein Multimerization, Spectrum Analysis, alpha-Synuclein

Journal Title

Molecules

Conference Name

Journal ISSN

1420-3049
1420-3049

Volume Title

Publisher

MDPI AG
Sponsorship
Wellcome Trust (094425/Z/10/Z)
MRC (MR/W01632X/1)