Small molecule-mediated stabilization of vesicle-associated helical Alpha-synuclein inhibits patogenic misfolding and aggregation

α-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson’s disease. While α-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded α-synuclein might therefore interfere with α-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of α-synuclein in solution, including the Parkinson’s disease drug selegiline, fail to interfere with misfolding of vesicle-bound α-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound α-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound α-synuclein opens new possibilities to target Parkinson’s disease and related synucleinopathiesFil: Fonseca Ornelas, Luis. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Eisbach, Sybille E.. University Medicine; AlemaniaFil: Paulat, Maria. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Giller, Karin. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Fernandez, Claudio Oscar. Universidad Nacional de Rosario; Argentina. Instituto de Investigaciones para el Descubrimiento de Farmacos de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Outeiro, Tiago F. University Medicine; Alemania. University Medical Center; AlemaniaFil: Becker, Stefan. Max Planck Institute for Biophysical Chemistry; AlemaniaFil: Zweckstetter, Markus. Max Planck Institute for Biophysical Chemistry; Alemania. University Medical Center; Alemania. German Center for Neurodegenerative Diseases; Alemani