Lipid Extraction by α-Synuclein Generates Semi-Transmembrane Defects and Lipoprotein Nanoparticles

Abstract

Modulations of synaptic membranes play an essential role in the physiological and pathological functions of the presynaptic protein α-synuclein (αSyn). Here we used solution atomic force microscopy (AFM) and electron paramagnetic resonance (EPR) spectroscopy to investigate membrane modulations caused by αSyn. We used several lipid bilayers to explore how different lipid species may regulate αSyn–membrane interactions. We found that at a protein-to-lipid ratio of ∼1/9, αSyn perturbed lipid bilayers by generating semi-transmembrane defects that only span one leaflet. In addition, αSyn coaggregates with lipid molecules to produce ∼10 nm-sized lipoprotein nanoparticles. The obtained AFM data are consistent with the apolipoprotein characteristic of αSyn. The role of anionic lipids was elucidated by comparing results from zwitterionic and anionic lipid bilayers. Specifically, our AFM measurements showed that anionic bilayers had a larger tendency of forming bilayer defects; similarly, our EPR measurements revealed that anionic bilayers exhibited more substantial changes in lipid chain mobility and bilayer polarity. We also studied the effect of cholesterol. We found that cholesterol increased the capability of αSyn in inducing bilayer defects and altering lipid chain mobility and bilayer polarity. These data can be explained by an increase in the lipid headgroup–headgroup spacing and/or specific cholesterol−αSyn interactions. Interestingly, we found an inhibitory effect of the cone-shaped phosphatidylethanolamine lipids on αSyn-induced bilayer remodeling. We explained our data by considering interlipid hydrogen-bonding that can stabilize bilayer organization and suppress lipid extraction. Our results of lipid-dependent membrane modulations are likely relevant to αSyn functioning.

Switching Cytolytic Nanopores into Antimicrobial Fractal Ruptures by a Single Side Chain Mutation

“…For bienA series the formation of conventional transmembrane pores was apparent in anionic SLBs. The pores appeared circular in shape ( Fig 2A, B ), with morphologies similar to circular pores reported for other peptides ( Fig S4 ), 21 , 28 , 40 , 41 and tended to expand and merge with larger defects observed for longer sequences ( Figs S5 & S6 ).…”

GM1 Ganglioside role in the interaction of Alpha-synuclein with lipid membranes: Morphology and structure

“…We can speculate of a similar membrane-interaction effect between monomers and oligomers with the difference that the aggregates species display a more aggressive behavior detectable already at low P/L ratio. Several mechanisms of interaction have been proposed for different oligomeric species involved in PD, such as pore formation and disruption of the bilayer [28], [63][64][65]. However, in our case the binding of oligomers does not seem to induce any of the mentioned effects, but seems to exhibit an interaction and/or protein accumulation in the upper monolayer of the membrane.…”

A Role of Cholesterol in Modulating the Binding of α-Synuclein to Synaptic-Like Vesicles

“…The relationship between cholesterol and PD is highly debated in the literature (Bosco et al, 2006;Liu et al, 2010), with several observations indicating a link between αS and the levels of cholesterol in cellular membranes (Fantini et al, 2011;van Maarschalkerweerd et al, 2014;Hsiao et al, 2017). Cholesterol was shown in particular to enhance the propensity of αS to induce the formation of defects in lipid bilayers (Pan et al, 2018), whereas αS can remodel cholesterol-enriched ternary membranes that mimic cellular raft-like domains (Leftin et al, 2013).…”