@article{597cf56463634a2c84363fbffc32f156,
title = "α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels.",
abstract = "The Parkinson{\textquoteright}s disease protein α-synuclein (αSyn) 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{\textquoteright}s cellular function(s) at the plasma membrane.",
author = "C{\'e}dric Eichmann and Alessandro Dema and Davide Mercadante and Philipp Selenko",
note = "We are grateful to Dr. Peter Schmieder and Monika Beerbaum for excellent maintenance of the NMR infrastructure at the Leibniz Institute of Molecular Pharmacology (FMP Berlin) and Dr. Tali Scherf for NMR infrastructure maintenance at the Weizmann Institute of Science. We thank Dr. Dmytro Puchkov (FMP Berlin) for assistance with negative-stain electron microscopy and Drs. Michael Krauss and Volker Haucke (FMP Berlin) for tools and reagents, helpful discussions throughout the project and useful feedback on the manuscript. Dr. Dorothea Fiedler (FMP Berlin) for sharing aliquots of IP6. We also thank Drs. Martin Lehmann (Cellular imaging, FMP Berlin) and Yoseph Addadi (Life Sciences Core Facilities, Weizmann Institute of Science) for excellent maintenance of imaging facilities and their support at the respective institutes. We acknowledge highly valuable input by Drs. Meir Schechter and Ronit Sharon, Hebrew University Jerusalem, especially with regard to time-resolved histamine experiments. We further thank them for kindly providing aliquots of the SK-MEL-2 cell line. We are grateful to Drs. Ori Avinoam, Hagen Hofmann (Weizmann) and Andres Binolfi (CONICET) for carefully reading the manuscript. C.E. was supported by a Swiss National Science Foundation (SNSF) Advanced Postdoc Mobility fellowship P300PA_160979. P.S. acknowledges funding by the European Research Council (ERC) Consolidator Grant NeuroInCellNMR (647474). TIRF imaging was made possible help and support of the de Picciotto Cancer Cell Observatory in memory of Wolfgang and Ruth Lesser. Work in the Selenko laboratory is supported by the Willner Family Foundation.",
year = "2021",
month = feb,
day = "15",
doi = "https://doi.org/10.7554/eLife.61951",
language = "الإنجليزيّة",
volume = "10",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}