TY - JOUR TI - α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels AU - Jacob, Reeba Susan AU - Eichmann, Cédric AU - Dema, Alessandro AU - Mercadante, Davide AU - Selenko, Philipp A2 - Brunger, Axel T A2 - Boudker, Olga A2 - Eliezer, David VL - 10 PY - 2021 DA - 2021/02/15 SP - e61951 C1 - eLife 2021;10:e61951 DO - 10.7554/eLife.61951 UR - https://doi.org/10.7554/eLife.61951 AB - The Parkinson’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 PM 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 function(s) at the plasma membrane. KW - human cell lines KW - A2780 KW - HeLa KW - SK-MEL-2 KW - SH-SY5Y JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -