title: Modulation of alpha-synuclein aggregation by dopamine analogs.
abstract: The action of dopamine on the aggregation of the unstructured alpha-synuclein (alpha-syn) protein may be linked to the pathogenesis of Parkinson's disease. Dopamine and its oxidation derivatives may inhibit alpha-syn aggregation by non-covalent binding. Exploiting this fact, we applied an integrated computational and experimental approach to find alternative ligands that might modulate the fibrillization of alpha-syn. Ligands structurally and electrostatically similar to dopamine were screened from an established library. Five analogs were selected for in vitro experimentation from the similarity ranked list of analogs. Molecular dynamics simulations showed they were, like dopamine, binding non-covalently to alpha-syn and, although much weaker than dopamine, they shared some of its binding properties. In vitro fibrillization assays were performed on these five dopamine analogs. Consistent with our predictions, analyses by atomic force and transmission electron microscopy revealed that all of the selected ligands affected the aggregation process, albeit to a varying and lesser extent than dopamine, used as the control ligand. The in silico/in vitro approach presented here emerges as a possible strategy for identifying ligands interfering with such a complex process as the fibrillization of an unstructured protein.
authors.affiliation: Department of Neurobiology, Scuola Internazionale Superiore di Studi Avanzati-International School for Advanced Studies, Trieste, Italy.
authors.forename: Diane
authors.initials: D
authors.lastname: Latawiec
authors.forename: Fernando
authors.initials: F
authors.lastname: Herrera
authors.forename: Alpan
authors.initials: A
authors.lastname: Bek
authors.forename: Valeria
authors.initials: V
authors.lastname: Losasso
authors.forename: Michela
authors.initials: M
authors.lastname: Candotti
authors.forename: Federico
authors.initials: F
authors.lastname: Benetti
authors.forename: Elvio
authors.initials: E
authors.lastname: Carlino
authors.forename: Agata
authors.initials: A
authors.lastname: Kranjc
authors.forename: Marco
authors.initials: M
authors.lastname: Lazzarino
authors.forename: Stefano
authors.initials: S
authors.lastname: Gustincich
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
mesh_terms: D002942:Circular Dichroism; D004298:Dopamine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D055672:Static Electricity; D014439:Tyramine / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D007211:Indoles; D008024:Ligands; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D014867:Water; C026785:5-hydroxyindole; D004298:Dopamine; D014439:Tyramine