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

Author

Listed:
  • 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”
    Imperial College London)

  • Giuliana Fusco

    (University of Cambridge)

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.

Suggested Citation

  • Wing K. Man & Bogachan Tahirbegi & Michail D. Vrettas & Swapan Preet & Liming Ying & Michele Vendruscolo & Alfonso De Simone & Giuliana Fusco, 2021. "The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21027-4
    DOI: 10.1038/s41467-021-21027-4
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    Cited by:

    1. Juan Manuel Ribes & Mitali P. Patel & Hazim A. Halim & Antonio Berretta & Sharon A. Tooze & Peter-Christian Klöhn, 2023. "Prion protein conversion at two distinct cellular sites precedes fibrillisation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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