title: ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis.
abstract: 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 phenotype remarkably similar to that of human ALS patients, to directly test the excitotoxicity hypothesis of ALS. Under basal culture conditions, MNs in mixed spinal cord cultures from the Cu/Zn-SOD mutant mice exhibited enhanced oxyradical production, lipid peroxidation, increased intracellular calcium levels, decreased intramitochondrial calcium levels, and mitochondrial dysfunction. MNs from the Cu/Zn-SOD mutant mice exhibited greatly increased vulnerability to glutamate toxicity mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors. The increased vulnerability of MNs from Cu/Zn-SOD mutant mice to glutamate toxicity was associated with enhanced oxyradical production, sustained elevations of intracellular calcium levels, and mitochondrial dysfunction. Pretreatment of cultures with vitamin E, nitric oxide-suppressing agents, peroxynitrite scavengers, and estrogen protected MNs from Cu/Zn-SOD mutant mice against excitotoxicity. Excitotoxin-induced 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 associated with Cu/Zn-SOD mutations may play an important role in disturbing calcium homeostasis and increasing oxyradical production, thereby increasing the vulnerability of MNs to excitotoxicity.
authors.affiliation: Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.
authors.forename: I I
authors.initials: II
authors.lastname: Kruman
authors.forename: W A
authors.initials: WA
authors.lastname: Pedersen
authors.forename: J E
authors.initials: JE
authors.lastname: Springer
authors.forename: M P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005609:Free Radicals; D018698:Glutamic Acid / Q000633:toxicity*; D006706:Homeostasis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015227:Lipid Peroxidation; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D009566:Nitrates / Q000378:metabolism; D018384:Oxidative Stress; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics*; D013481:Superoxides / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D005609:Free Radicals; D007093:Imidazoles; D009498:Neurotoxins; D009566:Nitrates; D013481:Superoxides; D014810:Vitamin E; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D020112:Rhodamine 123; C039642:peroxynitric acid; D018698:Glutamic Acid; D004958:Estradiol; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D013482:Superoxide Dismutase; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester