Constitutive overexpression of Cu/Zn superoxide dismutase exacerbates kainic acid-induced apoptosis of transgenic-Cu/Zn superoxide dismutase neurons.
Cu/Zn superoxide dismutase (Cu/Zn SOD) is a key enzyme in the metabolism of oxygen free radicals. The gene resides on chromosome 21 and is overexpressed in patients with Down syndrome. Cultured neurons of transgenic Cu/Zn SOD (Tg-Cu/Zn SOD) mice with elevated activity of Cu/Zn SOD were used to determine whether constitutive overexpression of Cu/Zn SOD creates an indigenous oxidative stress that predisposes the Tg-Cu/Zn SOD neurons to added insults. Neurons from three independently derived Tg-Cu/Zn SOD strains showed higher susceptibility than nontransgenic neurons to kainic acid (KA)-mediated excitotoxicity, reflected by an earlier onset and enhanced apoptotic cell death. This higher susceptibility of transgenic neurons to KA-mediated apoptosis was associated with a chronic prooxidant state that was manifested by reduced levels of cellular glutathione and altered [Ca2+]i homeostasis. The data are compatible with the thesis that overexpression of Cu/Zn SOD creates chronic oxidative stress in the transgenic neurons, which exacerbates their susceptibility to additional insults such as KA-mediated excitotoxicity.
Bar-Peled
O
O
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Korkotian
E
E
Segal
M
M
Groner
Y
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D005978:Glutathione / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000201:enzymology; D009474:Neurons / Q000201:enzymology*; D010084:Oxidation-Reduction; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000378:metabolism*
D013482:Superoxide Dismutase; D005978:Glutathione; D007608:Kainic Acid; D002118:Calcium