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α-Synuclein Oligomers Displace Monomeric α-Synuclein from Lipid Membranes.

Published version
Peer-reviewed

Repository DOI


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Authors

Šneiderienė, Greta 
Czekalska, Magdalena A 
Jayaram, Akhila K 

Abstract

Parkinson's disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein aggregates in the nervous system. While αS binding to membranes in its monomeric state is correlated to its physiological role, αS oligomerization and subsequent aberrant interactions with lipid bilayers have emerged as key steps in PD-associated neurotoxicity. However, little is known of the mechanisms that govern the interactions of oligomeric αS (OαS) with lipid membranes and the factors that modulate such interactions. This is in large part due to experimental challenges underlying studies of OαS-membrane interactions due to their dynamic and transient nature. Here, we address this challenge by using a suite of microfluidics-based assays that enable in-solution quantification of OαS-membrane interactions. We find that OαS bind more strongly to highly curved, rather than flat, lipid membranes. By comparing the membrane-binding properties of OαS and monomeric αS (MαS), we further demonstrate that OαS bind to membranes with up to 150-fold higher affinity than their monomeric counterparts. Moreover, OαS compete with and displace bound MαS from the membrane surface, suggesting that disruption to the functional binding of MαS to membranes may provide an additional toxicity mechanism in PD. These findings present a binding mechanism of oligomers to model membranes, which can potentially be targeted to inhibit the progression of PD.

Description

Publication status: Published

Keywords

Parkinson’s disease, aggregation, lipids, membranes, oligomers, α-synuclein, alpha-Synuclein, Lipid Bilayers, Humans, Protein Binding, Protein Multimerization

Journal Title

ACS Nano

Conference Name

Journal ISSN

1936-0851
1936-086X

Volume Title

18

Publisher

American Chemical Society (ACS)
Sponsorship
Engineering and Physical Sciences Research Council (EP/L015978/1)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (841466)
EPSRC (EP/S023046/1)
European Commission Horizon 2020 (H2020) ERC (101001615)
MRC (MR/W01632X/1)