CONSTITUTIVE OVEREXPRESSION OF CU ZN SUPEROXIDE-DISMUTASE EXACERBATESKAINIC ACID-INDUCED APOPTOSIS OF TRANSGENIC-CU/ZN SUPEROXIDE-DISMUTASE NEURONS/

Cu/Zn superoxide dismutase (Cu/Zn SOD) is a key enzyme in the metaboli sm of oxygen free radicals. The gene resides on chromosome 21 and is o verexpressed in patients with Down syndrome. Cultured neurons of trans genic Cu/Zn SOD (Tg-Cu/Zn SOD) mice with elevated activity of Cu/Zn SO D 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 deri ved Tg-Cu/Zn SOD strains showed higher susceptibility than nontransgen ic neurons to kainic acid (KA)-mediated excitotoxicity, reflected by a n earlier onset and enhanced apoptotic cell death. This higher suscept ibility 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 ar e 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 excitot oxicity.