α-Synuclein Insertion into Supported Lipid Bilayers As Seen by in Situ X-ray Reflectivity

Abstract

Large aggregates of misfolded -synuclein inside neuronal cells are the hallmarks of Parkinson's disease. The protein's natural function and its supposed toxicity, however, are believed to be closely related to its interaction with cell and vesicle membranes. Upon this interaction, the protein folds into an -helical structure and intercalates into the membrane. In this study, we focus on the changes in the lipid bilayer caused by this intrusion. In situ X-ray reflectivity was applied to determine the vertical density structure of the bilayer before and after exposure to -synuclein. It was found that the -synuclein insertion, wild type and E57K variant, caused a reduction in bilayer thickness. This effect may be one factor in the membrane pore formation ability of -synuclein. AbstractLarge aggregates of misfolded α-synuclein inside neuronal cells are the hallmarks of Parkinson's disease. The protein's natural function and its supposed toxicity, however, are believed to be closely related to its interaction with cell and vesicle membranes. Upon this interaction, the protein folds into an α-helical structure and intercalates into the membrane. In this study, we focus on the changes in the lipid bilayer caused by this intrusion. In situ X-ray reflectivity was applied to determine the vertical density structure of the bilayer before and after exposure to α-synuclein. It was found that the α-synuclein insertion, wild type and E57K variant, caused a reduction in bilayer thickness. This effect may be one factor in the membrane pore formation ability of α-synuclein.

Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes

“…Nevertheless, only one leaflet was disrupted in similar experiments carried out with a tethered bilayer 50 in the presence of α-synuclein. Whether the effect is on one or on both leaflets of the bilayer, the lipid depletion is consistent with the thinning of the bilayer observed in other studies, 13,51 and could be a mechanism of membrane permeation.…”

Structure Analysis of Amyloid Aggregates at Lipid Bilayers by Supercritical Angle Raman Microscopy

“…Although the formation of the bilayer could be confirmed, the current system could not collect the Raman scattering from a unilamellar bilayer with SAR or with UAR (Figure 1.a). The SLB had a thickness of about 4.93 nm 42 , which led to dominance of the supernatant water molecule background in the Raman signal despite their intrinsically low Raman cross-section scattering. The interfacial selectivity of the supercritical angle system prevented dominance of the water band at 3300 cm -1 , but the characteristic peaks of the lipid molecules were still not visible.…”

Oligomer modulator anle138b and related compounds in neurodegeneration and beyond

“…In addition to the drastic impact on α-synuclein behavior, α-synuclein/membrane interactions also have significant influence on lipid bilayer properties. Multiple studies have shown that monomeric and aggregated α-synuclein can induce various types of membrane disruption or rearrangement 4,161,165,170,171 . In case of phospholipid micelles, the addition of monomeric α-synuclein leads to a flattening and distortion of the surface curvature 4 .…”

“…Another study from the same group has shown concentrationdependent distortion of the PG/PC lipid bilayer by α-synuclein that was attributed to lipid tubule formation 165 . More recently, Hähl et al 171 have applied the X-ray reflectometry method that allows in situ characterization of lipid interfaces with Angstrom resolution. Thus, the evaluation of experimental data indicates a clear reduction of PS/PC bilayer thickness upon incubation with α-synuclein accompanied by the changes in the lipid packing.…”