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РЖ ВИНИТИ 76 (BI40) 95.12-04М7.151

McCord, J. M.
Mutant mice, Cu, Zn superoxide dismutase, and motor neuron degeneration: Discussion on the paper by Mark E. Gurney et al. [Text] / J. M. McCord // Science. - 1994. - Vol. 266, N 5190. - P1586-1587 . - ISSN 0036-8075
Перевод заглавия: Мыши, мутантные по Cu, Zn-супероксиддисмутазе, и дегенерация моторных нейронов: дискуссия по статье Mark E. Gurney и др.
Аннотация: We have reported that for any given rate of superoxide production there exists a concentration of SOD that will produce a minimum amount of oxidative stress and lipid peroxidation. This is a result of the paradoxical abilities of the superoxide radical to both initiate and terminate lipid peroxidation (4). (Initiation is indirect, by the liberation and reduction of iron.) Thus, when exogenous SOD is used to restore oxidative balance to a tissue in oxidative stress, such as a postischemic isolated heart, it exhibits a relatively sharp bell-shaped dose-response curve (5). A unique concentration of the enzyme provides maximal protection; either more or less than this concentration leads to increased lipid peroxidation, increased biochemical markers of tissue damage, and loss of function. The transgenic "ALS mouse" expresses four times more SOD activity than a normal mouse. The oxidative stress and increased lipid peroxidation resulting from this degree of overexpression would be substantially greater than that produced by expression of half the normal concentration of SOD, judging from the bell-shaped dose response curves (5). This would occur regardless of whether the activity were a result of a mutant form of SOD or of the native enzyme. Why, then, does the ALS transgenic mouse develop symptoms of ALS when other mice transgenic for SOD do not develop these particular symptoms? Perhaps it is because the tissue distribution of an overexpressed transgene is variable and unpredictable, depending on where in the genome the transgene integrates. It may have nothing to do with the fact that the excess SOD activity happens to be of a mutant human variety. We and others have studied wild-type human SOD overexpressed at comparable levels in transgenic mice, yet have not found clinical signs of motor neuron disease (3, 5). Some of these mice have been folloed from zero to 2 years of age (5), whereas disease in most lines of mice expressing mutant SOD develops by 4 to months of age (3, 4). Because multiple lines of mice expressing at least two different mutations of SOD develop motor neuron disease, while multiple lines of mice expressing wild-type human SOD do not, the hypothesis that variability in transgene expression underlies disease seems unlikely. Our data do not address the important issue, raised by McCord and others, of the role that oxidative stress may play in familial ALS. The mutations found in affected families decrease SOD activity (2), whereas our mutant and wild-type transgenic lines have a three- to fourfold elevation in SOD activity (3). McCord cites literature showing that either an increase or decrease in SOD activity may cause oxidative damage. Such damage may be a cofactor in disease, but oxidative stress per se cannot account for our findings, as only the mutant enzyme causes clinical disease in transgenic mice. США, Dep. Cell and Mol. Biol., Northwestern Univ., Chicago, Il 60611. Библ. 15

ГРНТИ	76.03.49

ВИНИТИ 761.03.49.27.41
Рубрики: СУПЕРОКСИДДИСМУТАЗЫ
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