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

Inna I. Kruman, Ward A. Pedersen, Joe E. Springer, Mark P. Mattson

Research output: Contribution to journalArticle

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 α-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.

Original languageEnglish (US)
Pages (from-to)28-39
Number of pages12
JournalExperimental Neurology
Volume160
Issue number1
DOIs
StatePublished - Nov 1999
Externally publishedYes

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Motor Neurons
Oxidative Stress
Homeostasis
Calcium
Mutation
Glutamic Acid
Spinal Cord
Peroxynitrous Acid
Propionates
Neurotoxins
Vitamin E
Lipid Peroxidation
Nitric Oxide
Estrogens
Phenotype

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. / Kruman, Inna I.; Pedersen, Ward A.; Springer, Joe E.; Mattson, Mark P.

In: Experimental Neurology, Vol. 160, No. 1, 11.1999, p. 28-39.

Research output: Contribution to journalArticle

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