title: Small molecule-mediated stabilization of vesicle-associated helical α-synuclein inhibits pathogenic misfolding and aggregation.
abstract: 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 synucleinopathies.
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Luis
authors.initials: L
authors.lastname: Fonseca-Ornelas
authors.affiliation: Department of Neurodegeneration and Restorative Research, University Medicine, Waldweg 33, 37073 Göttingen, Germany.
authors.forename: Sybille E
authors.initials: SE
authors.lastname: Eisbach
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Paulat
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.affiliation: 1] Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR), Universidad Nacional de Rosario, 27 de Febrero 210 bis, S2002LRK- Rosario, Argentina [2] Instituto de Investigaciones para el Descubrimiento de Farmacos de Rosario-IIDEFAR, (CONICET-UNR), 27 de Febrero 210 bis, S2002LRK- Rosario, Argentina.
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Fernández
authors.affiliation: 1] Department of Neurodegeneration and Restorative Research, University Medicine, Waldweg 33, 37073 Göttingen, Germany [2] DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center, 37073 Göttingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: 1] Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany [2] DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center, 37073 Göttingen, Germany [3] German Center for Neurodegenerative Diseases (DZNE), Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000978:Antiparkinson Agents / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D012642:Selegiline / Q000737:chemistry / Q000378:metabolism; D013572:Synaptic Vesicles / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D007211:Indoles; D051844:alpha-Synuclein; D012642:Selegiline; C028418:tetrasulfophthalocyanine