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Structural basis of synaptic vesicle assembly promoted by α-synuclein

Author

Listed:
  • Giuliana Fusco

    (University of Cambridge)

  • Tillmann Pape

    (Imperial College London)

  • Amberley D. Stephens

    (University of Cambridge)

  • Pierre Mahou

    (University of Cambridge
    Present address: Laboratory for Optics and Biosciences, Ecole Polytechnique, Palaiseau, 91128 Cedex, France)

  • Ana Rita Costa

    (University of Cambridge)

  • Clemens F. Kaminski

    (University of Cambridge)

  • Gabriele S. Kaminski Schierle

    (University of Cambridge)

  • Michele Vendruscolo

    (University of Cambridge)

  • Gianluigi Veglia

    (Molecular Biology & Biophysics, University of Minnesota)

  • Christopher M. Dobson

    (University of Cambridge)

  • Alfonso De Simone

    (Imperial College London)

Abstract

α-synuclein (αS) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson’s disease. Although the specific function of αS is still unclear, a general consensus is forming that it has a key role in regulating the process of neurotransmitter release, which is associated with the mediation of synaptic vesicle interactions and assembly. Here we report the analysis of wild-type αS and two mutational variants linked to familial Parkinson’s disease to describe the structural basis of a molecular mechanism enabling αS to induce the clustering of synaptic vesicles. We provide support for this ‘double-anchor’ mechanism by rationally designing and experimentally testing a further mutational variant of αS engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of αS that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.

Suggested Citation

  • Giuliana Fusco & Tillmann Pape & Amberley D. Stephens & Pierre Mahou & Ana Rita Costa & Clemens F. Kaminski & Gabriele S. Kaminski Schierle & Michele Vendruscolo & Gianluigi Veglia & Christopher M. Do, 2016. "Structural basis of synaptic vesicle assembly promoted by α-synuclein," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12563
    DOI: 10.1038/ncomms12563
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    Cited by:

    1. Steven J. Roeters & Kris Strunge & Kasper B. Pedersen & Thaddeus W. Golbek & Mikkel Bregnhøj & Yuge Zhang & Yin Wang & Mingdong Dong & Janni Nielsen & Daniel E. Otzen & Birgit Schiøtt & Tobias Weidner, 2023. "Elevated concentrations cause upright alpha-synuclein conformation at lipid interfaces," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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