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

Wing K. Man, Bogachan Tahirbegi, Michail D. Vrettas, Swapan Preet, Liming Ying, Michele Vendruscolo, Alfonso De Simone () and Giuliana Fusco ()
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Wing K. Man: University of Cambridge
Bogachan Tahirbegi: Molecular Sciences Research Hub, White City Campus
Michail D. Vrettas: University of Naples “Federico II”
Swapan Preet: University of Cambridge
Liming Ying: National Heart and Lung Institute, Imperial College London, Molecular Sciences Research Hub, White City Campus
Michele Vendruscolo: University of Cambridge
Alfonso De Simone: University of Naples “Federico II”
Giuliana Fusco: University of Cambridge

Nature Communications, 2021, vol. 12, issue 1, 1-10

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.

Date: 2021
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DOI: 10.1038/s41467-021-21027-4

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