title: Mechanism of membrane interaction and disruption by α-synuclein.
abstract: Parkinson's disease is a common progressive neurodegenerative condition, characterized by the deposition of amyloid fibrils as Lewy bodies in the substantia nigra of affected individuals. These insoluble aggregates predominantly consist of the protein α-synuclein. There is increasing evidence suggesting that the aggregation of α-synuclein is influenced by lipid membranes and, vice versa, the membrane integrity is severely affected by the presence of bound aggregates. Here, using the surface-sensitive imaging technique supercritical angle fluorescence microscopy and Förster resonance energy transfer, we report the direct observation of α-synuclein aggregation on supported lipid bilayers. Both the wild-type and the two mutant forms of α-synuclein studied, namely, the familiar variant A53T and the designed highly toxic variant E57K, were found to follow the same mechanism of polymerization and membrane damage. This mechanism involved the extraction of lipids from the bilayer and their clustering around growing α-synuclein aggregates. Despite all three isoforms following the same pathway, the extent of aggregation and their effect on the bilayers was seen to be variant and concentration dependent. Both A53T and E57K formed cross-β-sheet aggregates and damaged the membrane at submicromolar concentrations. The wild-type also formed aggregates in this range; however, the extent of membrane disruption was greatly reduced. The process of membrane damage could resemble part of the yet poorly understood cellular toxicity phenomenon in vivo.
authors: Institute of Physical Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors: Nicholas P
authors: NP
authors: Reynolds
authors: Alice
authors: A
authors: Soragni
authors: Michael
authors: M
authors: Rabe
authors: Dorinel
authors: D
authors: Verdes
authors: Ennio
authors: E
authors: Liverani
authors: Stephan
authors: S
authors: Handschin
authors: Roland
authors: R
authors: Riek
authors: Stefan
authors: S
authors: Seeger
mesh_terms: D031541:Fluorescence Resonance Energy Transfer; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D058105:Polymerization; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D051844:alpha-Synuclein