title: Small Molecules Detected by Second-Harmonic Generation Modulate the Conformation of Monomeric α-Synuclein and Reduce Its Aggregation in Cells.
abstract: Proteins are structurally dynamic molecules that perform specialized functions through unique conformational changes accessible in physiological environments. An ability to specifically and selectively control protein function via conformational modulation is an important goal for development of novel therapeutics and studies of protein mechanism in biological networks and disease. Here we applied a second-harmonic generation-based technique for studying protein conformation in solution and in real time to the intrinsically disordered, Parkinson disease related protein α-synuclein. From a fragment library, we identified small molecule modulators that bind to monomeric α-synuclein in vitro and significantly reduce α-synuclein aggregation in a neuronal cell culture model. Our results indicate that the conformation of α-synuclein is linked to the aggregation of protein in cells. They also provide support for a therapeutic strategy of targeting specific conformations of the protein to suppress or control its aggregation.
authors.affiliation: From Biodesy, Inc., South San Francisco, California 94080.
authors.forename: Ben
authors.initials: B
authors.lastname: Moree
authors.affiliation: the Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Guowei
authors.initials: G
authors.lastname: Yin
authors.affiliation: the Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, 37075 Göttingen, Germany, the Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, 37073 Göttingen, Germany, and.
authors.forename: Diana F
authors.initials: DF
authors.lastname: Lázaro
authors.affiliation: the Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany, the German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Munari
authors.affiliation: the Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Strohäker
authors.affiliation: the Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Giller
authors.affiliation: the Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: the Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, 37075 Göttingen, Germany, the Department of Neurodegeneration and Restorative Research, University Medical Center Göttingen, 37073 Göttingen, Germany, and.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: the Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany, the German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: From Biodesy, Inc., South San Francisco, California 94080, joshua.salafsky@biodesy.com.
authors.forename: Joshua
authors.initials: J
authors.lastname: Salafsky
mesh_terms: D000978:Antiparkinson Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000978:Antiparkinson Agents; D008024:Ligands; D066329:Protein Aggregates; D054852:Small Molecule Libraries; D051844:alpha-Synuclein
keywords: Parkinson disease; drug discovery; protein aggregation; protein conformation; protein drug interaction