Lipid bilayer disruption by oligomeric α-synuclein depends on bilayer charge and accessibility of the hydrophobic core

Abstract

Soluble oligomeric aggregates of alpha-synuclein have been implicated to play a central role in the pathogenesis of Parkinson's disease. Disruption and permeabilization of lipid bilayers by alpha-synuclein oligomers is postulated as a toxic mechanism, but the molecular details controlling the oligomer-membrane interaction are still unknown. Here we show that membrane disruption strongly depends on the accessibility of the hydrophobic membrane core and that charge interactions play an important but complex role. We systematically studied the influence of the physical membrane properties and solution conditions on lipid bilayer disruption by oligomers using a dye release assay. Varying the lipid headgroup composition revealed that membrane disruption only occurs for negatively charged bilayers. Furthermore, the electrostatic repulsion between the negatively charged alpha-synuclein and the negative surface charge of the bilayer inhibits vesicle disruption at low ionic strength. The disruption of negatively charged vesicles further depends on lipid packing parameters. Bilayer composition changes that result in an increased lipid headgroup spacing make vesicles more prone to disruption, suggesting that the accessibility of the bilayer hydrocarbon core modulates oligomer-membrane interaction. These data shed important new insights into the driving forces governing the highly debated process of oligomer-membrane interactions.

19F NMR studies of α‐synuclein‐membrane interactions

“…42 The presence of the double band in the POPC/POPG also makes the membrane more dynamic. 43,44 In summary, increasing the hydrophobic thickness and dynamics of the acyl chain lead to higher affinity.…”

Unraveling amyloid formation paths of Parkinson's disease protein α-synuclein triggered by anionic vesicles

“…Since amyloid fibrils were absent from aggregation reactions of this αS sample without vesicles, the 'contaminating' oligomers must depend on the vesicles for nucleation of amyloid formation. αS oligomers are described to interact with negatively charged bilayers and may cause membrane disruption (Fredenburg et al 2007;van Rooijen et al 2009). The molecular details of oligomer-membrane interactions and the effect on surrounding monomeric species by those interactions are still unclear.…”

Structural Insights into Amyloid Oligomers of the Parkinson Disease-related Protein α-Synuclein

“…We have previously used a simple method based on freeze-drying of concentrated protein samples (15) to generate stable ␤-sheet -rich wild-type oAS exhibiting vesicle disruption properties (13,29). As described under "Experimental Procedures," we optimized here the protocol to avoid undesirable dye-dye stacking interactions before lyophilization and fibril formation during the purification steps Labeled oAS showed the typical smeared band in a native gradient PAGE gel migrating concomitantly with the molecular mass marker ferritin of ϳ440 kDa, as the wild-type oligomers ( Fig.…”