posted on 2018-08-21, 13:03authored byJianjun Pan, Annalisa Dalzini, Nawal K. Khadka, Chinta M. Aryal, Likai Song
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.