title: Impaired antioxydative Keap1/Nrf2 system and the downstream stress protein responses in the motor neuron of ALS model mice.
abstract: The Kelch-like ECH-associated protein 1 (Keap1)/Nuclear erythroid 2-related factor 2 (Nrf2) system is the major cellular defense mechanism under oxidative stress, but the role in motor neuron degeneration under amyotrophic lateral sclerosis (ALS) pathology has not yet been fully elucidated. Here we examined temporal and spatial changes of Keap1, Nrf2, and their downstream stress response proteins heme oxgenase-1 (HO-1), glutathione, thioredoxin (TRX), and heat shock protein 70 (HSP70) throughout the course of motor neuron (MN) degeneration in the spinal cord of ALS model mice. Keap1 protein levels progressively decreased in the MN and anterior lumbar cord of ALS mice to 63% at early symptomatic 14 weeks and 58% at end symptomatic 18 weeks, while Nrf2 dramatically increased in the anterior lumbar cord with accumulation in the MN nucleus to 229% at 14 weeks and 471% at 18 weeks when glial like cells became also positive. In contrast, downstream stress response proteins such as HO-1, glutathione, TRX, and HSP70 showed only a small increase in MN with a significant increase to 149% to 280% in the number of glial-like cells after symptomatic 14 weeks. Our present observation suggests that MN selectively lost inductions of these important downstream protective proteins without regard to the Keap1/Nrf2 system activation, which could be a pivotal mechanism of neurodegenerative processes of ALS.
authors.affiliation: Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and pharmaceutical science, 2-5-1 Shikata-cho,Okayama, 700-8558, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mimoto
authors.forename: Kazunori
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Morimoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kurata
authors.forename: Kota
authors.initials: K
authors.lastname: Satoh
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013879:Thioredoxins; D051547:Heme Oxygenase-1; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D005978:Glutathione