title: Phenolic compounds prevent the oligomerization of α-synuclein and reduce synaptic toxicity.
abstract: Lewy bodies, mainly composed of α-synuclein (αS), are pathological hallmarks of Parkinson's disease and dementia with Lewy bodies. Epidemiological studies showed that green tea consumption or habitual intake of phenolic compounds reduced Parkinson's disease risk. We previously reported that phenolic compounds inhibited αS fibrillation and destabilized preformed αS fibrils. Cumulative evidence suggests that low-order αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (RA), nordihydroguaiaretic acid, and ferulic acid) on αS oligomerization. Using methods such as photo-induced cross-linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and RA inhibited αS oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N-terminal region of αS, whereas direct binding of RA to monomeric αS was not detected. Electrophysiological assays for long-term potentiation in mouse hippocampal slices revealed that Myr and RA ameliorated αS synaptic toxicity by inhibition of αS oligomerization. These results suggest that Myr and RA prevent the αS aggregation process, reducing the neurotoxicity of αS oligomers. To develop disease modifying therapies for α-synucleinopathies, we examined effects of phenolic compounds on α-synuclein (αS) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited αS oligomerization and secondary structure conversion. Myr and RA ameliorated αS synaptic toxicity on the experiment of long-term potentiation. Our results suggest that Myr and RA prevent αS aggregation process and reduce the neurotoxicity of αS oligomers. Phenolic compounds are good candidates of disease modifying drugs for α-synucleinopathies.
authors.affiliation: Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ono
authors.affiliation: System Emotional Science, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Takamura
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Mineyuki
authors.initials: M
authors.lastname: Mizuguchi
authors.affiliation: Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.|Department of Neurology, National Hospital Organization Iou Hospital, Kanazawa, Japan.
authors.forename: Tokuhei
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: System Emotional Science, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Nishijo
authors.affiliation: Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000682:Amyloid / Q000187:drug effects*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002934:Cinnamates / Q000494:pharmacology; D002942:Circular Dichroism; D003373:Coumaric Acids / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology; D053630:Depsides / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005419:Flavonoids / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D017774:Long-Term Potentiation; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010636:Phenols / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry / Q000187:drug effects*; D000097123:Rosmarinic Acid
chemical_list: D000682:Amyloid; D000975:Antioxidants; D002934:Cinnamates; D003373:Coumaric Acids; D003474:Curcumin; D053630:Depsides; D005419:Flavonoids; D009637:Masoprocol; D010636:Phenols; D051844:alpha-Synuclein; D000097123:Rosmarinic Acid; C040015:myricetin; C004999:ferulic acid
keywords: myricetin; oligomerization; phenolic compounds; rosmarinic acid; α-synuclein; α-synucleinopathies