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The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition

Published version
Peer-reviewed

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Authors

Man, Wing K. 
Tahirbegi, Bogachan 
Vrettas, Michail D.  ORCID logo  https://orcid.org/0000-0002-5456-3226
Preet, Swapan 

Abstract

Abstract: α-Synuclein (αS) is a presynaptic disordered protein whose aberrant aggregation is associated with Parkinson’s disease. The functional role of αS is still debated, although it has been involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs). We report here a detailed characterisation of the conformational properties of αS bound to the inner and outer leaflets of the presynaptic plasma membrane (PM), using small unilamellar vesicles. Our results suggest that αS preferentially binds the inner PM leaflet. On the basis of these studies we characterise in vitro a mechanism by which αS stabilises, in a concentration-dependent manner, the docking of SVs on the PM by establishing a dynamic link between the two membranes. The study then provides evidence that changes in the lipid composition of the PM, typically associated with neurodegenerative diseases, alter the modes of binding of αS, specifically in a segment of the sequence overlapping with the non-amyloid component region. Taken together, these results reveal how lipid composition modulates the interaction of αS with the PM and underlie its functional and pathological behaviours in vitro.

Description

Keywords

Article, /631/378/548/2589, /631/535/878, /692/699/375/365/1718, /140/131, /147, /123, article

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723

Volume Title

12

Publisher

Nature Publishing Group UK
Sponsorship
Leverhulme Trust (RPC-2015-345)
RCUK | Medical Research Council (MRC) (N000676)