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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 \u03b1S fibrillation and destabilized preformed \u03b1S fibrils. Cumulative evidence suggests that low\u2010order \u03b1S oligomers are neurotoxic and critical species in the pathogenesis of \u03b1\u2010synucleinopathies. To develop disease modifying therapies for \u03b1\u2010synucleinopathies, we examined effects of phenolic compounds (myricetin (Myr), curcumin, rosmarinic acid (\n                    <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\n                    ), nordihydroguaiaretic acid, and ferulic acid) on \u03b1S oligomerization. Using methods such as photo\u2010induced cross\u2010linking of unmodified proteins, circular dichroism spectroscopy, the electron microscope, and the atomic force microscope, we showed that Myr and\n                    <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\n                    inhibited \u03b1S oligomerization and secondary structure conversion. The nuclear magnetic resonance analysis revealed that Myr directly bound to the N\u2010terminal region of \u03b1S, whereas direct binding of\n                    <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\n                    to monomeric \u03b1S was not detected. Electrophysiological assays for long\u2010term potentiation in mouse hippocampal slices revealed that Myr and\n                    <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\n                    ameliorated \u03b1S synaptic toxicity by inhibition of \u03b1S oligomerization. These results suggest that Myr and\n                    <jats:styled-content style=\"fixed-case\">RA<\/jats:styled-content>\n                    prevent the \u03b1S aggregation process, reducing the neurotoxicity of \u03b1S oligomers.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13180-fig-0007-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>\n                  <jats:p>To develop disease modifying therapies for \u03b1\u2010synucleinopathies, we examined effects of phenolic compounds on \u03b1\u2010synuclein (\u03b1S) oligomerization. Phenolic compounds, especially Myricetin (Myr) and Rosmarinic acid (RA), inhibited \u03b1S oligomerization and secondary structure conversion. Myr and RA ameliorated \u03b1S synaptic toxicity on the experiment of long\u2010term potentiation. Our results suggest that Myr and RA prevent \u03b1S aggregation process and reduce the neurotoxicity of \u03b1S oligomers. Phenolic compounds are good candidates of disease modifying drugs for \u03b1\u2010synucleinopathies.<\/jats:p>","DOI":"10.1111\/jnc.13180","type":"journal-article","created":{"date-parts":[[2015,5,27]],"date-time":"2015-05-27T10:34:35Z","timestamp":1432722875000},"page":"943-955","source":"Crossref","is-referenced-by-count":99,"title":["Phenolic compounds prevent the oligomerization of \u03b1\u2010synuclein and reduce synaptic toxicity"],"prefix":"10.1111","volume":"134","author":[{"given":"Ryoichi","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurobiology of Aging Kanazawa University Graduate School of Medical Science Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenjiro","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurobiology of Aging Kanazawa University Graduate School of Medical Science Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusaku","family":"Takamura","sequence":"additional","affiliation":[{"name":"System Emotional Science Graduate School of Medicine and Pharmaceutical Science University of Toyama Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mineyuki","family":"Mizuguchi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences University of Toyama Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tokuhei","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurobiology of Aging Kanazawa University Graduate School of Medical Science Kanazawa Japan"},{"name":"Department of Neurology National Hospital Organization Iou Hospital Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisao","family":"Nishijo","sequence":"additional","affiliation":[{"name":"System Emotional Science Graduate School of Medicine and Pharmaceutical Science University of Toyama Toyama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahito","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurobiology of Aging Kanazawa University Graduate School of Medical Science Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,6,17]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.524520"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/mp700113r"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.1052"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910723107"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar000214l"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-04-0838"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-004-0956-9"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1315346111"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.65.5.781"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.2012.00484.x"},{"key":"e_1_2_7_12_1","first-page":"2895","article-title":"Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high\u2010risk or pre\u2010malignant lesions","volume":"21","author":"Cheng A. 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