The Effect of α-Synuclein on Lipid Membrane Properties Characterized by Molecular Dynamics and Atomic Force Microscopy

Abstract

The protein α-synuclein (αSyn), primarily recognized for its link to neurodegenerative disorders, has multiple reported functions. One well-established role of αSyn is its ability to bind and remodel lipid membranes. This ability has been characterized in synthetic lipid bilayers and has been observed both in cellular and in vivo models. The native environment of αSyn—the presynaptic terminal of neurons—contains mitochondria and synaptic vesicles, which have unique membranes that differ from previously studied models. The goal of this dissertation was to characterize how lipids enriched in synaptic vesicles and mitochondria affect how αSyn changes membrane properties. First, molecular dynamics (MD) simulations of synaptic vesicle-mimic bilayers showed how lipids with polyunsaturated fatty acids modify membrane properties and interact with αSyn. Next, tubulation experiments were combined with MD simulations to explore how αSyn remodels bilayers containing cardiolipin and phosphatidylethanolamine, two lipids enriched in mitochondria. Finally, methods were developed to characterize lipid vesicle mechanical properties using pulsed force mode (PFM) atomic force microscopy (AFM). This work provides insight into the specifics of how αSyn affects the properties of synaptic vesicle and mitochondrial membranes and demonstrates how PFM-AFM can identify the mechanical properties of lipid vesicles.