title: Alteration in intracellular calcium homeostasis reduces motor neuronal viability expressing mutated Cu/Zn superoxide dismutase through a nitric oxide/guanylyl cyclase cGMP cascade.
abstract: Missense mutations in the human Cu/Zn superoxide dismutase gene (SOD-1) cause many cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS). The accumulation of intracellular calcium is one of the primary mechanisms of motor neuronal degeneration associated with mutations in SOD-1. In order to investigate the effect of various calcium modulators and the SOD-1 mutation on neuronal death, we tested motoneuron-neuroblastoma hybrid (VSC 4.1) cells constitutively expressing human SOD-1 gene with mutations (A4V, G93A) or wild-type. These cells were treated with endogenous calcium releaser (ryanodine, thapsigargin, cyclic ADP-ribose) or calcium mobilizer through cell membrane (4-bromo-calcium ionophore A23187). In particular, calcium ionophore reduced survival in the cells expressing mutant SOD-1. Cell death was associated with increased nitric oxide (NO) generation. This toxicity was attenuated when a nitric oxide synthase (NOS) inhibitor was added. Exogenous NOadministration (S-nitrosoglutathione) also induced cell death. The NO-dependent guanylyl cyclase-cGMP cascade inhibitor protected the mutant cells from the toxic effects of calcium ionophore. Our data suggests that motoneuron degeneration with the SOD-1 mutation may be mediated by calcium dysregulation, particularly by the exogenous calcium influx. This process induces oxidative stress generation that results in motor neuronal death through the guanylyl cyclase-cGMP dependent cascade.
authors.affiliation: Department of Neurology, Seoul National University College of Medicine, 28 Yongon-Dong, Jongno-Gu, Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Manho
authors.initials: M
authors.lastname: Kim
authors.forename: Sung Hun
authors.initials: SH
authors.lastname: Kim
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Sung
authors.forename: Kwang-Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics*; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000201:enzymology; D007476:Ionophores / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000494:pharmacology; D020030:Nitric Oxide Donors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D007476:Ionophores; D020030:Nitric Oxide Donors; D012433:Ryanodine; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D006152:Cyclic GMP