Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels

The Parkinson's disease protein [alpha]-synuclein ([alpha]Syn) promotes membrane fusion and fission by interacting with various negatively charged phospholipids. Despite postulated roles in endocytosis and exocytosis, plasma membrane (PM) interactions of [alpha]Syn are poorly understood. Here,...

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Bibliographic Details
Published in:eLife 2021-02, Vol.10
Main Authors: Jacob, Reeba Susan, Eichmann, Cédric, Dema, Alessandro, Mercadante, Davide, Selenko, Philipp
Format: Article
Language:English
Subjects:
Cell membranes
Lipids
Phosphatases
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Summary:The Parkinson's disease protein [alpha]-synuclein ([alpha]Syn) promotes membrane fusion and fission by interacting with various negatively charged phospholipids. Despite postulated roles in endocytosis and exocytosis, plasma membrane (PM) interactions of [alpha]Syn are poorly understood. Here, we show that phosphatidylinositol 4,5-bisphosphate (PIP.sub.2) and phosphatidylinositol 3,4,5-trisphosphate (PIP.sub.3), two highly acidic components of inner PM leaflets, mediate PM localization of endogenous pools of [alpha]Syn in A2780, HeLa, SK-MEL-2, and differentiated and undifferentiated neuronal SH-SY5Y cells. We demonstrate that [alpha]Syn binds to reconstituted PIP.sub.2 membranes in a helical conformation in vitro and that PIP.sub.2 synthesizing kinases and hydrolyzing phosphatases reversibly redistribute [alpha]Syn in cells. We further delineate that [alpha]Syn-PM targeting follows phosphoinositide-3 kinase (PI3K)-dependent changes of cellular PIP.sub.2 and PIP.sub.3 levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to [alpha]Syn's function(s) at the plasma membrane.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.61951