Cargando…

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

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 phosphatid...

Descripción completa

Detalles Bibliográficos
Autores principales: Jacob, Reeba Susan, Eichmann, Cédric, Dema, Alessandro, Mercadante, Davide, Selenko, Philipp
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929559/
https://www.ncbi.nlm.nih.gov/pubmed/33587036
http://dx.doi.org/10.7554/eLife.61951
_version_ 1783659940694458368
author Jacob, Reeba Susan
Eichmann, Cédric
Dema, Alessandro
Mercadante, Davide
Selenko, Philipp
author_facet Jacob, Reeba Susan
Eichmann, Cédric
Dema, Alessandro
Mercadante, Davide
Selenko, Philipp
author_sort Jacob, Reeba Susan
collection PubMed
description 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(2)) and phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), 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(2) membranes in a helical conformation in vitro and that PIP(2) 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(2) and PIP(3) levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to αSyn’s function(s) at the plasma membrane.
format Online
Article
Text
id pubmed-7929559
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-79295592021-03-04 α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels Jacob, Reeba Susan Eichmann, Cédric Dema, Alessandro Mercadante, Davide Selenko, Philipp eLife Neuroscience 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(2)) and phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), 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(2) membranes in a helical conformation in vitro and that PIP(2) 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(2) and PIP(3) levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to αSyn’s function(s) at the plasma membrane. eLife Sciences Publications, Ltd 2021-02-15 /pmc/articles/PMC7929559/ /pubmed/33587036 http://dx.doi.org/10.7554/eLife.61951 Text en © 2021, Jacob et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Jacob, Reeba Susan
Eichmann, Cédric
Dema, Alessandro
Mercadante, Davide
Selenko, Philipp
α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
title α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
title_full α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
title_fullStr α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
title_full_unstemmed α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
title_short α-Synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
title_sort α-synuclein plasma membrane localization correlates with cellular phosphatidylinositol polyphosphate levels
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929559/
https://www.ncbi.nlm.nih.gov/pubmed/33587036
http://dx.doi.org/10.7554/eLife.61951
work_keys_str_mv AT jacobreebasusan asynucleinplasmamembranelocalizationcorrelateswithcellularphosphatidylinositolpolyphosphatelevels
AT eichmanncedric asynucleinplasmamembranelocalizationcorrelateswithcellularphosphatidylinositolpolyphosphatelevels
AT demaalessandro asynucleinplasmamembranelocalizationcorrelateswithcellularphosphatidylinositolpolyphosphatelevels
AT mercadantedavide asynucleinplasmamembranelocalizationcorrelateswithcellularphosphatidylinositolpolyphosphatelevels
AT selenkophilipp asynucleinplasmamembranelocalizationcorrelateswithcellularphosphatidylinositolpolyphosphatelevels