α-Synuclein Plasma Membrane Localization Correlates with Cellular Phosphatidylinositol Polyphosphate Levels

Overview

Journal Elife

Specialty Biology

Date 2021 Feb 15

PMID 33587036

Citations 11

Authors

Reeba Susan Jacob

Cedric Eichmann

Alessandro Dema

Davide Mercadante

Philipp Selenko

Affiliations

Soon will be listed here.

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) and phosphatidylinositol 3,4,5-trisphosphate (PIP), 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 membranes in a helical conformation in vitro and that PIP 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 and PIP levels, which collectively suggests that phosphatidylinositol polyphosphates contribute to αSyn's function(s) at the plasma membrane.

Citing Articles

Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson's disease patients mutated in TMEM175.

Carrillo F, Ghirimoldi M, Fortunato G, Palomba N, Ianiro L, De Giorgis V NPJ Parkinsons Dis. 2025; 11(1):23.

PMID: 39856101 PMC: 11760379. DOI: 10.1038/s41531-024-00853-5.

Lipids and α-Synuclein: adding further variables to the equation.

Schepers J, Loser T, Behl C Front Mol Biosci. 2024; 11:1455817.

PMID: 39188788 PMC: 11345258. DOI: 10.3389/fmolb.2024.1455817.

Protein modification in neurodegenerative diseases.

Ramazi S, Dadzadi M, Darvazi M, Seddigh N, Allahverdi A MedComm (2020). 2024; 5(8):e674.

PMID: 39105197 PMC: 11298556. DOI: 10.1002/mco2.674.

Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.

Burre J, Edwards R, Halliday G, Lang A, Lashuel H, Melki R Mov Disord. 2024; 39(10):1663-1678.

PMID: 38946200 PMC: 11808831. DOI: 10.1002/mds.29897.

α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity.

Horvath J, Casas M, Kutchukian C, Sanchez S, Pergande M, Cologna S Cell Rep. 2023; 42(10):113244.

PMID: 37838947 PMC: 11010634. DOI: 10.1016/j.celrep.2023.113244.

References

Krauss M, Kukhtina V, Pechstein A, Haucke V . Stimulation of phosphatidylinositol kinase type I-mediated phosphatidylinositol (4,5)-bisphosphate synthesis by AP-2mu-cargo complexes. Proc Natl Acad Sci U S A. 2006; 103(32):11934-9. PMC: 1567676. DOI: 10.1073/pnas.0510306103. View

Dettmer U . Rationally Designed Variants of α-Synuclein Illuminate Its Structural Properties in Health and Disease. Front Neurosci. 2018; 12:623. PMC: 6167557. DOI: 10.3389/fnins.2018.00623. View

Saheki Y, Bian X, Schauder C, Sawaki Y, Surma M, Klose C . Control of plasma membrane lipid homeostasis by the extended synaptotagmins. Nat Cell Biol. 2016; 18(5):504-15. PMC: 4848133. DOI: 10.1038/ncb3339. View

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T . Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012; 9(7):676-82. PMC: 3855844. DOI: 10.1038/nmeth.2019. View

Shahmoradian S, Lewis A, Genoud C, Hench J, Moors T, Navarro P . Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes. Nat Neurosci. 2019; 22(7):1099-1109. DOI: 10.1038/s41593-019-0423-2. View

Bilkova E, Pleskot R, Rissanen S, Sun S, Czogalla A, Cwiklik L . Calcium Directly Regulates Phosphatidylinositol 4,5-Bisphosphate Headgroup Conformation and Recognition. J Am Chem Soc. 2017; 139(11):4019-4024. PMC: 5364432. DOI: 10.1021/jacs.6b11760. View

Schechter M, Grigoletto J, Abd-Elhadi S, Glickstein H, Friedman A, Serrano G . A role for α-Synuclein in axon growth and its implications in corticostriatal glutamatergic plasticity in Parkinson's disease. Mol Neurodegener. 2020; 15(1):24. PMC: 7104492. DOI: 10.1186/s13024-020-00370-y. View

Narayanan V, Scarlata S . Membrane binding and self-association of alpha-synucleins. Biochemistry. 2001; 40(33):9927-34. DOI: 10.1021/bi002952n. View

Mahul-Mellier A, Burtscher J, Maharjan N, Weerens L, Croisier M, Kuttler F . The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc Natl Acad Sci U S A. 2020; 117(9):4971-4982. PMC: 7060668. DOI: 10.1073/pnas.1913904117. View

10.

Kaur U, Lee J . Unroofing site-specific α-synuclein-lipid interactions at the plasma membrane. Proc Natl Acad Sci U S A. 2020; 117(32):18977-18983. PMC: 7430991. DOI: 10.1073/pnas.2006291117. View

11.

Binolfi A, Limatola A, Verzini S, Kosten J, Theillet F, Rose H . Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites. Nat Commun. 2016; 7:10251. PMC: 4737712. DOI: 10.1038/ncomms10251. View

12.

Schanda P, Kupce E, Brutscher B . SOFAST-HMQC experiments for recording two-dimensional heteronuclear correlation spectra of proteins within a few seconds. J Biomol NMR. 2005; 33(4):199-211. DOI: 10.1007/s10858-005-4425-x. View

13.

Mizuguchi H, Terao T, Kitai M, Ikeda M, Yoshimura Y, Das A . Involvement of protein kinase Cdelta/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 (PARP-1) signaling pathway in histamine-induced up-regulation of histamine H1 receptor gene expression in HeLa cells. J Biol Chem. 2011; 286(35):30542-30551. PMC: 3162414. DOI: 10.1074/jbc.M111.253104. View

14.

Pinot M, Vanni S, Pagnotta S, Lacas-Gervais S, Payet L, Ferreira T . Lipid cell biology. Polyunsaturated phospholipids facilitate membrane deformation and fission by endocytic proteins. Science. 2014; 345(6197):693-7. DOI: 10.1126/science.1255288. View

15.

Gray A, van der Kaay J, Downes C . The pleckstrin homology domains of protein kinase B and GRP1 (general receptor for phosphoinositides-1) are sensitive and selective probes for the cellular detection of phosphatidylinositol 3,4-bisphosphate and/or phosphatidylinositol.... Biochem J. 1999; 344 Pt 3:929-36. PMC: 1220718. View

16.

Perrin R, WOODS W, Clayton D, George J . Interaction of human alpha-Synuclein and Parkinson's disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J Biol Chem. 2000; 275(44):34393-8. DOI: 10.1074/jbc.M004851200. View

17.

Milosevic I, Sorensen J, Lang T, Krauss M, Nagy G, Haucke V . Plasmalemmal phosphatidylinositol-4,5-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells. J Neurosci. 2005; 25(10):2557-65. PMC: 6725155. DOI: 10.1523/JNEUROSCI.3761-04.2005. View

18.

Varnai P, Balla T . Visualization of phosphoinositides that bind pleckstrin homology domains: calcium- and agonist-induced dynamic changes and relationship to myo-[3H]inositol-labeled phosphoinositide pools. J Cell Biol. 1998; 143(2):501-10. PMC: 2132833. DOI: 10.1083/jcb.143.2.501. View

19.

Pfenninger K . Plasma membrane expansion: a neuron's Herculean task. Nat Rev Neurosci. 2009; 10(4):251-61. DOI: 10.1038/nrn2593. View

20.

Bilanges B, Posor Y, Vanhaesebroeck B . PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol. 2019; 20(9):515-534. DOI: 10.1038/s41580-019-0129-z. View