Alpha-synuclein is an intrinsically disordered protein abundant in presynaptic terminals in neurons and in synaptic vesicles. The protein’s interaction with lipid bilayers is important for its normal physiological function, and is also believed to play a role in stimulating its pathological aggregation and deposition as Lewy bodies in Parkinson’s disease. Alpha-synuclein binds preferentially to lipids with acidic head groups and to high-curvature vesicles, and can modulate membrane curvature. We investigated the interaction of alpha-synuclein with vesicles of 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) or 1,2-dilauroyl-sn-glycero-3-phospho-L-serine (DLPS). Using nanoparticle tracking along with electron microscopy, we demonstrate that alpha-synuclein induces extensive vesicle disruption and membrane remodeling into discoids, tubules, and ribbons with vesicles made of DLPS but not DOPS. Coarse-grained molecular dynamics simulations revealed that adsorption of alpha-synuclein to DLPS but not DOPS vesicles induced vesicle elongation and redistribution of protein to the highly curved poles, a process that could drive protein aggregation. In agreement with this hypothesis, DLPS but not DOPS strongly stimulated alpha-synuclein aggregation. Our results provide new insights into the critical contribution of bilayer stability in the membrane response to alpha-synuclein adsorption, and in stimulation of aggregation.

Role of bilayer stability in membrane remodeling and stimulation of alpha-synuclein aggregation

ACS Spring Meeting 2021

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