title: Oxidative stress induced by glutathione depletion reproduces pathological modifications of TDP-43 linked to TDP-43 proteinopathies.
abstract: TAR DNA-binding protein 43 (TDP-43) is a major component of ubiquitin-positive inclusion of TDP-43 proteinopathies including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions, which is now referred to as FTLD-TDP. TDP-43 in the aberrant inclusion is known to be hyperphosphorylated at C-terminal sites, to be truncated at the N-terminal region, and to re-distribute from nucleus to cytoplasm or neurite. The pathogenic role of these modifications, however, has not been clarified. Furthermore, there is no evidence about the initial cause of these modifications. Herein we show that ethacrynic acid (EA), which is able to increase cellular oxidative stress through glutathione depletion, induces TDP-43 C-terminal phosphorylation at serine 403/404 and 409/410, insolubilization, C-terminal fragmentation, and cytoplasmic distribution in NSC34 cells and primary cortical neurons. In the investigation using a nonphosphorylable mutant of TDP-43, there was no evidence that C-terminal phosphorylation of TDP-43 contributes to its solubility or distribution under EA induction. Our findings suggest that oxidative stress induced by glutathione depletion is associated with the process of the pathological TDP-43 modifications and provide new insight for TDP-43 proteinopathies.
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Iguchi
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Takagi
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Niwa
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002934:Cinnamates / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D005978:Glutathione / Q000172:deficiency*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C493177:4-(4-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D002934:Cinnamates; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D016877:Oxidants; D017382:Reactive Oxygen Species; C518786:tetrabromocinnamic acid; D049452:Green Fluorescent Proteins; D012694:Serine; C007293:DAPI; D006861:Hydrogen Peroxide; D005978:Glutathione; D004976:Ethacrynic Acid; D000111:Acetylcysteine