Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative damage and antioxidant defences: relevance to Down's syndrome and familial amyotrophic lateral sclerosis.
Patients with Down's syndrome (DS) show elevated levels of copper, zinc-containing superoxide dismutase (SOD1) and appear to have increased lipid peroxidation and oxidative damage to DNA as well as elevated glutathione peroxidase activity. Increasing SOD1 levels by gene transfection in NT-2 and SK-N-MC cell lines also led to a rise in glutathione peroxidase activity, but this was nevertheless accompanied by decreased proliferation rates, increased lipid peroxidation and protein carbonyls, and a trend to a rise in 8-hydroxyguanine and protein-bound 3-nitrotyrosine. Transfection of these cell lines with DNA encoding two mutant SOD1 enzymes (G37R and G85R) associated with familial amyotrophic lateral sclerosis (FALS), produced similar, but more severe changes, i.e. even lower growth rates, higher lipid peroxidation, 3-nitrotyrosine and protein carbonyl levels, decreased GSH levels, raised GSSG levels and higher glutathione peroxidase activities. Since G85R has little SOD activity, these changes cannot be related to increased O(2)(-) scavenging. In no case was SOD2 (mitochondrial Mn-SOD) level altered. Our cellular systems reproduce many of the biochemical changes observed in patients with DS or ALS, and in transgenic mice overexpressing mutant SOD1. They also show the potentially deleterious effects of SOD1 overexpression on cellular proliferation, which may be relevant to abnormal development in DS.
Lee
M
M
Wolfson Centre for Age-Related Diseases, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College London, UK.
Hyun
D
D
Jenner
P
P
Halliwell
B
B
D000447:Aldehydes / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007659:Ketones / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D009154:Mutation; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D018243:Teratocarcinoma / Q000201:enzymology / Q000235:genetics; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000447:Aldehydes; D000975:Antioxidants; D007659:Ketones; C000606290:SOD1 protein, human; C002744:3-nitrotyrosine; D014443:Tyrosine; C024829:8-hydroxyguanine; D006147:Guanine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005978:Glutathione; D019803:Glutathione Disulfide