Lautenschläger, Janin, Stephens, Amberley D., Fusco, Giuliana, Ströhl, Florian, Curry, Nathan, Zacharopoulou, Maria, Michel, Claire H., Laine, Romain, Nespovitaya, Nadezhda, Fantham, Marcus, Pinotsi, Dorothea, Zago, Wagner, Fraser, Paul, Tandon, Anurag, St George-Hyslop, Peter, Rees, Eric, Phillips, Jonathan J., De Simone, Alfonso, Kaminski, Clemens F., Kaminski Schierle, Gabriele S., Stephens, Amberley D [0000-0002-7303-6392], Ströhl, Florian [0000-0002-2603-0780], St George-Hyslop, Peter [0000-0003-0796-7209], Phillips, Jonathan J [0000-0002-5361-9582], Kaminski, Clemens F [0000-0002-5194-0962], Schierle, Gabriele S Kaminski [0000-0002-1843-2202], and Apollo - University of Cambridge Repository
Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N terminus, which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C terminus of alpha-synuclein, therewith increasing its lipid-binding capacity. Using CEST-NMR, we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N terminus, already known from studies on SUVs, and additionally via its C terminus, which is regulated by the binding of calcium. Indeed, dSTORM on synaptosomes shows that calcium mediates the localization of alpha-synuclein at the pre-synaptic terminal, and an imbalance in calcium or alpha-synuclein can cause synaptic vesicle clustering, as seen ex vivo and in vitro. This study provides a new view on the binding of alpha-synuclein to synaptic vesicles, which might also affect our understanding of synucleinopathies., Alpha-synuclein is associated with neuronal dysfunction in Parkinson’s disease. This study shows that alpha-synuclein interacts with neuronal synaptic vesicles in a calcium-dependent fashion, and this interaction is important for synaptic vesicle clustering.