title: Homocysteine induces oxidative cytotoxicity in Cu,Zn-superoxide dismutase mutant motor neuronal cell.
abstract: Mutations in human Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism of late-onset disease manifestation despite the innate mutation has no clear explanation. The relationship between homocysteine (HC) and amyotrophic lateral sclerosis (ALS) has not been investigated, in spite of the similarity in their pathogenesis. We investigated the effect of HC on the motor neuronal cell-line transfected with SOD1 of either wild-type or one of two mutant forms (G93A and A4V). In the MTT assay, HC induced significant cytotoxicity in A4V, but not in G93A, as compared with wild-type, even at the physiological concentration of 10 microM. This HC-induced cytotoxicity was inhibited by the antioxidant trolox and the Cu (I) chelator bathocuproinedisulfonate. Here we show that the vulnerability of the A4 V mutant involves the cytotoxic copper-mediated pathway, and that HC may be a lifelong precipitating factor in some forms of FALS, suggesting the possible treatment modality with vitamin supplements.
authors.affiliation: Department of Neurology, and Clinical Research Institute, and Neuroscience Research Institute in SNU Medical Research Center, Seoul National University College of Medicine, 28 Yongon-Dong, Jongno-Gu 110-744, Korea.
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Sung
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Smi
authors.initials: S
authors.lastname: Choi-Kwon
authors.forename: JoungHee
authors.initials: J
authors.lastname: Lee
authors.forename: Manho
authors.initials: M
authors.lastname: Kim
authors.forename: Kwang-Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006710:Homocysteine / Q000633:toxicity*; D006801:Humans; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D009154:Mutation / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D006710:Homocysteine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase