ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis

We employed a mouse model of ALS, in which overexpression of a familial ALS -linked Cu/Zn-SOD mutation leads to progressive MN loss and a clinical phen otype remarkably similar to that of human ALS patients, to directly test th e excitotoxicity hypothesis of ALS. Under basal culture conditions, MNs in mixed spinal cord cultures from the Cu/Zn-SOD mutant mice exhibited enhance d oxyradical production, lipid peroxidation, increased intracellular calciu m levels, decreased intramitochondrial calcium levels, and mitochondrial dy sfunction. MNs from the Cu/Zn-SOD mutant mice exhibited greatly increased v ulnerability to glutamate toxicity mediated by alpha-amino-3-hydroxy-5-meth ylisoxazole-4-propionate receptors. The increased vulnerability of MNs from Cu/Zn-SOD mutant mice to glutamate toxicity was associated with enhanced o xyradical production, sustained elevations of intracellular calcium levels, and mitochondrial dysfunction. Pretreatment of cultures with vitamin E, ni tric oxide-suppressing agents, peroxynitrite scavengers, and estrogen prote cted MNs from Cu/Zn-SOD mutant mice against excitotoxicity. Excitotoxin-ind uced degeneration of spinal cord MNs in adult mice was more extensive in Cu /Zn-SOD mutant mice than in wild-type mice. The mitochondrial dysfunction a ssociated with Cu/Zn-SOD mutations may play an important role in disturbing calcium homeostasis and increasing oxyradical production, thereby increasi ng the vulnerability of MNs to excitotoxicity, (C) 1999 Academic Press.