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Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation.


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Authors

Galvagnion, Céline 
Buell, Alexander K 
Michaels, Thomas CT 
Vendruscolo, Michele  ORCID logo  https://orcid.org/0000-0002-3616-1610

Abstract

α-Synuclein (α-syn) is a 140-residue intrinsically disordered protein that is involved in neuronal and synaptic vesicle plasticity, but its aggregation to form amyloid fibrils is the hallmark of Parkinson's disease (PD). The interaction between α-syn and lipid surfaces is believed to be a key feature for mediation of its normal function, but under other circumstances it is able to modulate amyloid fibril formation. Using a combination of experimental and theoretical approaches, we identify the mechanism through which facile aggregation of α-syn is induced under conditions where it binds a lipid bilayer, and we show that the rate of primary nucleation can be enhanced by three orders of magnitude or more under such conditions. These results reveal the key role that membrane interactions can have in triggering conversion of α-syn from its soluble state to the aggregated state that is associated with neurodegeneration and to its associated disease states.

Description

Keywords

Amyloid, Fluorescence Polarization, Kinetics, Lipid Bilayers, Membrane Lipids, Parkinson Disease, alpha-Synuclein

Journal Title

Nat Chem Biol

Conference Name

Journal ISSN

1552-4450
1552-4469

Volume Title

11

Publisher

Nature Publishing Group
Sponsorship
Wellcome Trust (094425/Z/10/Z)
Biotechnology and Biological Sciences Research Council (BB/H003843/1)
Biotechnology and Biological Sciences Research Council (BB/J002119/1)
Wellcome Trust (089703/Z/09/Z)
European Research Council (337969)
This work was supported by the UK BBSRC and the Wellcome Trust (CMD, TPJK, MV), the Frances and Augustus Newman Foundation (TPJK), Magdalene College, Cambridge (AKB) , St John’s College, Cambridge (TCTM), the Cambridge Home and EU Scholarship Scheme (GM), Elan Pharmaceuticals (CMD, TPJK, MV, CG) and the Leverhulme Trust (AKB).