α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33587036.
- Also identified by DOI 10.7554/eLife.61951 and PMC identifier 7929559.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 (PIP<sub>2</sub>) and phosphatidylinositol 3,4,5-trisphosphate (PIP<sub>3</sub>), 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 PIP<sub>2</sub> membranes in a helical conformation in vitro and that PIP<sub>2</sub> 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 PIP<sub>2</sub> and PIP<sub>3</sub> levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to αSyn's function(s) at the plasma membrane.
Medical subject headings
- Cell Membrane
- Parkinson Disease
- Phosphatidylinositol 4,5-Diphosphate
- Phosphatidylinositol Phosphates
- alpha-Synuclein