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    Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics

    Year: 2013

    Journal: ACS Chem. Neurosci., 2013, 4 (10), pp 1339–1351, 20140104

    Authors: Erik Hellstrand *1, Marie Grey 2, Marie-Louise Ainalem 2, John Ankner 4, V. Trevor Forsyth 5 6, Giovanna Fragneto 5, Michael Haertlein 5, Marie-Therese Dauvergne 5, Hanna Nilsson 1, Patrik Brundin 7 8, Sara Linse 9, Tommy Nylander 2, and Emma Sparr 2

    Last authors: Emma Sparr

    Organizations: 1 Biophysical Chemistry, Department of Chemistry, Lund University, SE-22100 Lund, Sweden 2 Physical Chemistry, Department of Chemistry, Lund University, SE-22100 Lund, Sweden 3 European Spallation Source ESS, SE-22100 Lund, Sweden 4 Oak Ridge National Laboratory, Spallation Neutron Source, Oak Ridge, Tennessee 37831, United States 5 Institut Laue-Langevin, 6, rue Jules Horowitz, 38042 Grenoble, France 7 Neuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC B11, 221 84 Lund, Sweden 8 Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, Michigan 49503, United States 9 Biochemistry and Structural Biology, Department of Chemistry, Lund University, SE-22100 Lund, Sweden 6 EPSAM/ISTM, Keele University, Staffordshire, ST5 5BG, UK

    Country: USA, US, United States, United States of America, America, Sverige, Sweden, France, England, UK

    An amyloid form of the protein α-synuclein is the major component of the intraneuronal inclusions called Lewy bodies, which are the neuropathological hallmark of Parkinson’s disease (PD). α-Synuclein is known to associate with anionic lipid membranes, and interactions between aggregating α-synuclein and cellular membranes are thought to be important for PD pathology. We have studied the molecular determinants for adsorption of monomeric α-synuclein to planar model lipid membranes composed of zwitterionic phosphatidylcholine alone or in a mixture with anionic phosphatidylserine (relevant for plasma membranes) or anionic cardiolipin (relevant for mitochondrial membranes). We studied the adsorption of the protein to supported bilayers, the position of the protein within and outside the bilayer, and structural changes in the model membranes using two complementary techniques—quartz crystal microbalance with dissipation monitoring, and neutron reflectometry. We found that the interaction and adsorbed conformation depend on membrane charge, protein charge, and electrostatic screening. The results imply that α-synuclein adsorbs in the headgroup region of anionic lipid bilayers with extensions into the bulk but does not penetrate deeply into or across the hydrophobic acyl chain region. The adsorption to anionic bilayers leads to a small perturbation of the acyl chain packing that is independent of anionic headgroup identity. We also explored the effect of changing the area per headgroup in the lipid bilayer by comparing model systems with different degrees of acyl chain saturation. An increase in area per lipid headgroup leads to an increase in the level of α-synuclein adsorption with a reduced water content in the acyl chain layer. In conclusion, the association of α-synuclein to membranes and its adsorbed conformation are of electrostatic origin, combined with van der Waals interactions, but with a very weak correlation to the molecular structure of the anionic lipid headgroup. The perturbation of the acyl chain packing upon monomeric protein adsorption favors association with unsaturated phospholipids preferentially found in the neuronal membrane.