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ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis.
Exp Neurol. 1999 Nov; 160(1):28-39.EN

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+Show Affiliations

Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10630188

Citation

Kruman, I I., et al. "ALS-linked Cu/Zn-SOD Mutation Increases Vulnerability of Motor Neurons to Excitotoxicity By a Mechanism Involving Increased Oxidative Stress and Perturbed Calcium Homeostasis." Experimental Neurology, vol. 160, no. 1, 1999, pp. 28-39.
Kruman II, Pedersen WA, Springer JE, et al. ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. Exp Neurol. 1999;160(1):28-39.
Kruman, I. I., Pedersen, W. A., Springer, J. E., & Mattson, M. P. (1999). ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. Experimental Neurology, 160(1), 28-39.
Kruman II, et al. ALS-linked Cu/Zn-SOD Mutation Increases Vulnerability of Motor Neurons to Excitotoxicity By a Mechanism Involving Increased Oxidative Stress and Perturbed Calcium Homeostasis. Exp Neurol. 1999;160(1):28-39. PubMed PMID: 10630188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis. AU - Kruman,I I, AU - Pedersen,W A, AU - Springer,J E, AU - Mattson,M P, PY - 2000/1/12/pubmed PY - 2000/1/12/medline PY - 2000/1/12/entrez SP - 28 EP - 39 JF - Experimental neurology JO - Exp Neurol VL - 160 IS - 1 N2 - 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. SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/10630188/ALS_linked_Cu/Zn_SOD_mutation_increases_vulnerability_of_motor_neurons_to_excitotoxicity_by_a_mechanism_involving_increased_oxidative_stress_and_perturbed_calcium_homeostasis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4886(99)97190-X DB - PRIME DP - Unbound Medicine ER -