title: How epigallocatechin gallate can inhibit α-synuclein oligomer toxicity in vitro.
abstract: Oligomeric species of various proteins are linked to the pathogenesis of different neurodegenerative disorders. Consequently, there is intense focus on the discovery of novel inhibitors, e.g. small molecules and antibodies, to inhibit the formation and block the toxicity of oligomers. In Parkinson disease, the protein α-synuclein (αSN) forms cytotoxic oligomers. The flavonoid epigallocatechin gallate (EGCG) has previously been shown to redirect the aggregation of αSN monomers and remodel αSN amyloid fibrils into disordered oligomers. Here, we dissect EGCG's mechanism of action. EGCG inhibits the ability of preformed oligomers to permeabilize vesicles and induce cytotoxicity in a rat brain cell line. However, EGCG does not affect oligomer size distribution or secondary structure. Rather, EGCG immobilizes the C-terminal region and moderately reduces the degree of binding of oligomers to membranes. We interpret our data to mean that the oligomer acts by destabilizing the membrane rather than by direct pore formation. This suggests that reduction (but not complete abolition) of the membrane affinity of the oligomer is sufficient to prevent cytotoxicity.
authors.affiliation: From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Lorenzen
authors.affiliation: From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures.
authors.forename: Søren B
authors.initials: SB
authors.lastname: Nielsen
authors.affiliation: From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Departments of Chemistry.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshimura
authors.affiliation: From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Vad
authors.affiliation: From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures.
authors.forename: Camilla Bertel
authors.initials: CB
authors.lastname: Andersen
authors.affiliation: Biomedicine-Medical Biochemistry, and.
authors.forename: Cristine
authors.initials: C
authors.lastname: Betzer
authors.affiliation: From the Interdisciplinary Nanoscience Center, Departments of Chemistry.
authors.forename: Jørn D
authors.initials: JD
authors.lastname: Kaspersen
authors.affiliation: Biomedicine-Medical Immunology, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Gunna
authors.initials: G
authors.lastname: Christiansen
authors.affiliation: From the Interdisciplinary Nanoscience Center, Departments of Chemistry.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Biomedicine-Medical Biochemistry, and.
authors.forename: Poul Henning
authors.initials: PH
authors.lastname: Jensen
authors.affiliation: From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, Departments of Chemistry.
authors.forename: Frans A A
authors.initials: FA
authors.lastname: Mulder
authors.affiliation: From the Interdisciplinary Nanoscience Center, Center for Insoluble Protein Structures, dao@inano.au.dk.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Otzen
mesh_terms: D001704:Biopolymers / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D002152:Calorimetry, Differential Scanning; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002463:Cell Membrane Permeability; D002942:Circular Dichroism; D066298:In Vitro Techniques; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity
chemical_list: D001704:Biopolymers; D051844:alpha-Synuclein; D002392:Catechin; C045651:epigallocatechin gallate
keywords: Dynamic Light Scattering; EGCG; Isothermal Titration Calorimetry (ITC); Membrane; Nuclear Magnetic Resonance (NMR); Oligomer; Toxicity; X-ray Scattering; α-Synuclein