title: α-Synuclein Oligomers Stabilize Pre-Existing Defects in Supported Bilayers and Propagate Membrane Damage in a Fractal-Like Pattern.
abstract: Phospholipid vesicles are commonly used to get insights into the mechanism by which oligomers of amyloidogenic proteins damage membranes. Oligomers of the protein α-synuclein (αS) are thought to create pores in phospholipid vesicles containing a high amount of anionic phospholipids but fail to damage vesicle membranes at low surface charge densities. The current understanding of how αS oligomers damage the membranes is thus incomplete. This incomplete understanding may, in part, result from the choice of model membrane systems. The use of free-standing membranes such as vesicles may interfere with the unraveling of some damage mechanisms because the line tension at the edge of a membrane defect or pore ensures defect closure. Here, we have used supported lipid bilayers (SLBs) of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPC/POPS) to study the membrane damage caused by αS oligomers. Although αS oligomers were not able to initiate the disruption of POPC/POPS vesicles or intact SLBs, oligomers did stabilize and enlarge pre-existing SLB defects. The increased exposure of lipid acyl chains at the edges of defects very likely facilitates membrane-oligomer interactions, resulting in the growth of fractal domains devoid of lipids. Concomitant with the appearance of the fractal membrane damage patterns, lipids appear in solution, directly implicating αS oligomers in the observed lipid extraction. The growth of the membrane damage patterns is not limited by the binding of lipids to the oligomer. The analysis of the shape and growth of the lipid-free domains suggests the involvement of an oligomer-dependent diffusion-limited extraction mechanism. The observed αS oligomer-induced propagation of membrane defects offers new insights into the mechanisms by which αS oligomers can contribute to the loss in membrane integrity.
authors: Nanobiophysics Group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, Department of Science and Technology, University of Twente , 7500 AE Enschede, The Netherlands.
authors: Himanshu
authors: H
authors: Chaudhary
authors: Nanobiophysics Group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, Department of Science and Technology, University of Twente , 7500 AE Enschede, The Netherlands.|Nanoscale Biophysics Group, FOM Institute AMOLF , Science Park 104, 1098 XG Amsterdam, The Netherlands.
authors: Aditya
authors: A
authors: Iyer
authors: Nanobiophysics Group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, Department of Science and Technology, University of Twente , 7500 AE Enschede, The Netherlands.|Nanoscale Biophysics Group, FOM Institute AMOLF , Science Park 104, 1098 XG Amsterdam, The Netherlands.|Vrije Universiteit Amsterdam , De Boelelaan 1105, 1081 HV Amsterdam, The Netherlands.
authors: Vinod
authors: V
authors: Subramaniam
authors: Nanobiophysics Group, MESA+ Institute for Nanotechnology and MIRA Institute for Biomedical Technology and Technical Medicine, Department of Science and Technology, University of Twente , 7500 AE Enschede, The Netherlands.
authors: Mireille M A E
authors: MM
authors: Claessens
mesh_terms: D002462:Cell Membrane / Q000737:chemistry* / Q000473:pathology; D017709:Fractals; D008051:Lipid Bilayers / Q000737:chemistry; D018625:Microscopy, Atomic Force; D018613:Microscopy, Confocal; D010713:Phosphatidylcholines / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D059008:Time-Lapse Imaging; D053835:Unilamellar Liposomes / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D053835:Unilamellar Liposomes; D051844:alpha-Synuclein; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine