Elevated "hydroxyl radical" generation in vivo in an animal model of amyotrophic lateral sclerosis.
Mutations in the enzyme copper/zinc superoxide dismutase-1 (SOD1) are associated with familial amyotrophic lateral sclerosis (FALS). The means by which the mutations cause FALS appears to be due to an adverse property of the mutant SOD1 protein that may involve increased generation of free radicals. We used in vivo microdialysis to measure the conversion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid (3,4-DHBA) as a measure of "hydroxyl radical-like" production in transgenic amyotrophic lateral sclerosis (ALS) mice with the G93A mutation as well as littermate controls. The conversion of 4-hydroxybenzoic acid to 3,4-DHBA was significantly increased in the striatum of transgenic ALS mice at baseline but not in mice overexpressing wild-type human SOD1. Following administration of 3-nitropropionic acid 3,4-DHBA generation was significantly increased as compared with baseline, and the increase in the transgenic ALS mice was significantly greater than those in controls, whereas the increase in mice overexpressing wild-type human SOD1 was significantly attenuated. The present results provide in vivo evidence that expression of mutations in SOD1 can lead to increased generation of "hydroxyl radical-like" activity, which further implicates oxidative damage in the pathogenesis of ALS.
Bogdanov
M B
MB
Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Ramos
L E
LE
Xu
Z
Z
Beal
M F
MF
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D006801:Humans; D062385:Hydroxybenzoates / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D017551:Microdialysis; D009498:Neurotoxins / Q000494:pharmacology; D009574:Nitro Compounds; D010226:Parabens / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D062385:Hydroxybenzoates; D009498:Neurotoxins; D009574:Nitro Compounds; D010226:Parabens; D011422:Propionates; C000606290:SOD1 protein, human; D017665:Hydroxyl Radical; C009091:protocatechuic acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C038193:4-hydroxybenzoic acid; C015392:3-nitropropionic acid