α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels

Abstract

The Parkinson's disease protein α-synuclein (aSyn) promotes membrane fusion and fission by interacting with various negatively charged phospholipids. Despite postulated roles in endocytosis and exocytosis, plasma membrane (PM) interactions of αSyn are poorly understood. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3), two highly acidic components of inner PM leaflets, mediate plasma membrane localization of endogenous pools of αSyn in A2780, HeLa, SK-MEL-2 and differentiated and undifferentiated neuronal SH-SY5Y cells. We demonstrate that αSyn binds to reconstituted PIP2-membranes in a helical conformation in vitro and that PIP2 synthesizing kinases and hydrolyzing phosphatases reversibly redistribute αSyn in cells. We further delineate that αSyn-PM targeting follows phosphoinositide-3 kinase (PI3K)-dependent changes of cellular PIP2 and PIP3 levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to αSyn's cellular function(s) at the plasma membrane.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1,2,3 and all Supplementary Figures.

Article and author information

Author details

  1. Reeba Susan Jacob

    Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Cedric Eichmann

    Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Alessandro Dema

    Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Davide Mercadante

    Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Philipp Selenko

    Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
    For correspondence
    philipp.selenko@weizmann.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2590-5899

Funding

European Research Council (647474)

  • Philipp Selenko

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Axel T Brunger, Stanford University, United States

Version history

  1. Received: August 10, 2020
  2. Accepted: February 12, 2021
  3. Accepted Manuscript published: February 15, 2021 (version 1)
  4. Version of Record published: March 3, 2021 (version 2)

Copyright

© 2021, Jacob et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Reeba Susan Jacob
  2. Cedric Eichmann
  3. Alessandro Dema
  4. Davide Mercadante
  5. Philipp Selenko
(2021)
α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
eLife 10:e61951.
https://doi.org/10.7554/eLife.61951

Share this article

https://doi.org/10.7554/eLife.61951

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