Structural characterisation of α-synuclein-membrane interactions and the resulting aggregation using small angle scattering

Céline Galvagnion*, Abigail Barclay, Katarzyna Makasewicz, Frederik Ravnkilde Marlet, Martine Moulin, Juliette M Devos, Sara Linse, Anne Martel, Lionel Porcar, Emma Sparr, Martin Cramer Pedersen, Felix Roosen-Runge, Lise Arleth, Alexander K Buell

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The presence of amyloid fibrils is a hallmark of several neurodegenerative diseases. Some amyloidogenic proteins, such as α-synuclein and amyloid β, interact with lipids, and this interaction can strongly favour the formation of amyloid fibrils. In particular the primary nucleation step, i.e. the de novo formation of amyloid fibrils, has been shown to be accelerated by lipids. However, the exact mechanism of this acceleration is still mostly unclear. Here we use a range of scattering methods, such as dynamic light scattering (DLS) and small angle X-ray and neutron scattering (SAXS and SANS) to obtain structural information on the binding of α-synuclein to model membranes formed from negatively charged lipids and their co-assembly into amyloid fibrils. We find that the model membranes take an active role in the reaction. The binding of α synuclein to the model membranes immediately induces a major structural change in the lipid assembly, which leads to a break-up into small and mostly disc- or rod-like lipid-protein particles. This transition can be reversed by temperature changes or proteolytic protein removal. Incubation of the small lipid-α-synuclein particles for several hours, however, leads to amyloid fibril formation, whereby the lipids are incorporated into the amyloid fibrils.

Original languageEnglish
JournalPhysical chemistry chemical physics : PCCP
Volume26
Pages (from-to)10998-11013
ISSN1463-9076
DOIs
Publication statusPublished - 2024

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