Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity

被引:25
作者
Cudkowicz, ME
Pastusza, KA
Sapp, PC
Mathews, RK
Leahy, J
Pasinelli, P
Francis, JW
Jiang, D
Andersen, JK
Brown, RH
机构
[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurol Clin Trials Unit, Boston, MA 02115 USA
[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Day Neuromuscular Lab, Boston, MA 02115 USA
[3] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA
[4] Univ So Calif, Ethel Percy Andrus Gerontol Ctr, Div Neurogerontol, Los Angeles, CA 90089 USA
[5] Univ So Calif, Program Neurobiol, Los Angeles, CA 90089 USA
[6] Buck Inst Age Res, Novato, CA USA
关键词
D O I
10.1212/WNL.59.5.729
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Objective: Transgenic mice that overexpress a human gene encoding mutant cytosolic superoxide dismutase (SOD1) develop a progressive motor neuron loss that resembles human ALS. Why mutant SOD1 initiates motor neuron death is unknown. One hypothesis proposes that the mutant molecule has enhanced peroxidase activity, reducing hydrogen peroxide (H2O2) to form toxic hydroxyl adducts on critical targets. To test this hypothesis, the authors generated transgenic ALS mice with altered levels of glutathione peroxidase (GSHPx), the major soluble enzyme that detoxifies H2O2. Methods: SOD1(G93A) ALS mice were bred with mice bearing a murine GSHPx transgene that have a four-fold elevation in brain GSHPx levels and with mice having targeted inactivation of the GSHPx gene and reduced brain GSHPx activity. Results: Survival was not prolonged in ALS mice with elevated brain GSHPx activity (p = 0.09). ALS mice with decreased GSHPx brain activity (20% of normal) showed no acceleration of the disease course (p = 0.89). The age at disease onset in the ALS mice was unaffected by brain GSHPx activity. Conclusion: The level of GSHPx activity in the CNS of transgenic ALS mice does not play a critical role in the development of motor neuron disease.
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页码:729 / 734
页数:6
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