Alpha-Synuclein (aSyn) is an abundant protein in neurons, localized to the presynaptic terminal. In solution, aSyn is intrinsically disordered, but it adopts an alpha-helical conformation upon binding to lipid bilayers. Its ability to modulate membrane curvature may be key to its physiological roles. Beyond its normal function, aSyn has attracted considerable attention because of the role of aSyn aggregates in Parkinson’s disease.<br/><br/>We interrogated the interaction of aSyn with unilamellar vesicles of DOPS (1,2-dioleoyl-sn-glycerol-3-phospho-L-serine) and DLPS (1,2-dilauroyl-sn-glycero-3-phospho-L-serine). Phosphatidylserine is the most abundant anionic lipid in eukaryotic membranes and aSyn is well-known to interact with charged head groups.  We describe the novel use of nanoparticle tracking analysis (NTA) to quantify aSyn-vesicle interaction. The technique allows measurement of a particle-by-particle size distribution and scattering intensity, as well as particle number concentration. Experiments were carried out at pH 7.4 and 100 mM NaCl. Immediately upon addition of aSyn to DOPS, we observed a small but measurable increase in the hydrodynamic diameter of liposomes, but no change in number concentration. In contrast, with DLPS we observed a modest decrease in liposome diameter and a slow but substantial decrease in liposome number concentration that continued for hours. Furthermore, we saw a significant drop in the ratio of intensity/hydrodynamic diameter for DLPS but not DOPS. We hypothesized that the decrease in this ratio was due to a change in particle shape. By TEM, aSyn induced a minor shape change in DOPS liposomes from spherical to prolate ‘footballs’. In contrast, aSyn induced substantial tubulation and large-scale membrane restructuring in DLPS. MD simulations showed that aSyn strongly induces negative curvature in DLPS but not DOPS, consistent with tubulation. Furthermore, aSyn molecules congregated in regions of high curvature, increasing the local concentration. Over time, aSyn with DLPS but not DOPS developed a small thioflavin T-positive signal, suggesting the formation of amyloid-like aggregates. At slightly lower pH and ionic strength (pH 6.5, 20 mM phosphate), a strongly positive ThT signal was detected with aSyn plus DLPS and a much weaker signal with aSyn plus DOPS. These results suggest that aSyn preferentially remodels less-stable vesicles and that, conversely, membrane remodeling supports conditions that can lead to aggregation.

Alpha-synuclein-mediated membrane remodeling

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.