a-Synuclein is an abundant protein found in the presynaptic terminal of neuronal axons but its physiological function remains unclear, even as the dysfunction of a-Synuclein is fundamentally linked to Parkinson’s. While a-Synuclein is accepted to peripherally bind to the membrane of synaptic vesicles (organelles that sequester neurotransmitters), there is increasing evidence that a-Synuclein can subsequently regulate diffusion dynamics of synaptic vesicles through an unknown mechanism. Here, we present strong evidence that a-Synuclein (at biologically relevant concentrations) disrupts inter-membrane interactions between synaptic vesicle-mimics at physiological salt and temperature conditions through a combination of synchrotron small-angle X-ray scattering and X-ray photon correlation spectroscopy (XPCS). In designing synaptic vesicle-mimics with membranes encapsulating a silica nanoparticle core, not only do we enforce membrane curvature and charge at the physiological limit necessary for a-Synuclein binding, but the high scattering cross-section of silica nanoparticles makes feasible the direct measurement of synaptic vesicle-mimic diffusivity via state-of-the-art XPCS. With increasing addition of a-Synuclein, our synaptic vesicle-mimics transition from a lower-than-expected diffusive state (with attractions most likely occurring due to charge fluctuations) to the expected Brownian diffusion of non-interacting colloidal particles. This transition is highly indicative of a-Synuclein sterically-stabilizing synaptic vesicle-mimics, most likely due to its projecting, highly-charged, unstructured C-terminal domain. In unveiling a novel, biophysical function for the C-terminal domain of a-Synuclein, we will demonstrate the effect of phosphorylation of a-Synuclein at S129, the post-translation modification most associated with Parkinson’s, and discuss how a-Synuclein may affect the super-structure of synaptic vesicles within the neuron.

a-Synuclein disrupts inter-membrane interactions

2019 Spring National Meeting

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