title: Glycogen synthase kinase-3β activation mediates rotenone-induced cytotoxicity with the involvement of microtubule destabilization.
abstract: Rotenone, a mitochondrial complex I inhibitor, has been used to generate animal and cell culture models of Parkinson's disease. Recent studies suggest that microtubule destabilization causes selective dopaminergic neuronal loss. In this study, we investigated glycogen synthase kinase-3β (GSK3β) involvement in rotenone-induced microtubule destabilization. Rotenone-induced cytotoxicity in SH-SY5Y cells was attenuated by the GSK3β inhibitor SB216763. Tau, a microtubule-associated protein and substrate for GSK3β, has been implicated in the pathogenesis of tauopathies such as Alzheimer's disease. Rotenone induced an increase in phosphorylated tau, the effect of which was attenuated by concomitant treatment with SB216763. Rotenone treatment also decreased tau expression in the microtubule fraction and increased tau expression in the cytosol fraction. These effects were suppressed by SB216763, which suggests that rotenone reduces the capacity of tau to bind microtubules. Rotenone treatment increased the amount of free tubulin and reduced the amount of polymerized tubulin, indicating that rotenone destabilizes microtubules. Rotenone-induced microtubule destabilization was suppressed by SB216763 and taxol, a microtubule stabilizer. Taxol prevented rotenone-induced cytotoxicity and morphological changes. Taken together, these results suggest that rotenone-induced cytotoxicity is mediated by microtubule destabilization via GSK3β activation, and that microtubule destabilization is caused by reduction in the binding capacity of tau to microtubules, which is a result of tau phosphorylation via GSK3β activation.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Hongo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kihara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Niidome
authors.forename: Hachiro
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D045744:Cell Line, Tumor; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D007211:Indoles; D008301:Maleimides; D017382:Reactive Oxygen Species; C417521:SB 216763; D050257:Tubulin Modulators; D016875:tau Proteins; D012402:Rotenone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D042967:Electron Transport Complex I; D017239:Paclitaxel