Liu R, Althaus J S, Ellerbrock B R, Becker D A, Gurney M E
Department of Biological Sciences, Western Michigan University, Kalamazoo, USA.
Ann Neurol. 1998 Nov;44(5):763-70. doi: 10.1002/ana.410440510.
Mutations of the SOD1 gene encoding copper/zinc superoxide dismutase (CuZnSOD) cause an inherited form of amyotrophic lateral sclerosis. When expressed in transgenic mice, the same SOD1 mutations cause progressive loss of spinal motor neurons with consequent paralysis and death. In vitro biochemical studies indicate that SOD1 mutations enhance free radical generation by the mutant enzyme. We investigated those findings in vivo by using a novel, brain-permeable spin trap, azulenyl nitrone. Reaction of azulenyl nitrone with a free radical forms a nitroxide adduct that then fragments to yield the corresponding azulenyl aldehyde. Transgenic mice expressing mutant SOD1-G93A show enhanced free radical content in spinal cord but not brain. This correlates with tissue-specific differences in the level of transgene expression. In spinal cord, the increase in free radical content is in direct proportion to the age-dependent increase in mutant human CuZnSOD expression. This increase precedes motor neuron degeneration. The higher level of human CuZnSOD expression seen in spinal cord compared with brain, and consequent difference in free radical generation, provides a basis for understanding the selective vulnerability of the spinal cord in this disease model.
编码铜锌超氧化物歧化酶（CuZnSOD）的SOD1基因突变会导致一种遗传性肌萎缩侧索硬化症。当在转基因小鼠中表达时，相同的SOD1突变会导致脊髓运动神经元逐渐丧失，继而出现瘫痪和死亡。体外生化研究表明，SOD1突变会增强突变酶产生自由基的能力。我们使用一种新型的、可透过血脑屏障的自旋捕捉剂——薁基硝酮，在体内对这些发现进行了研究。薁基硝酮与自由基反应会形成一种氮氧加合物，该加合物随后会分解产生相应的薁基醛。表达突变型SOD1 - G93A的转基因小鼠脊髓中的自由基含量增加，但脑中没有。这与转基因表达水平的组织特异性差异相关。在脊髓中，自由基含量的增加与突变型人CuZnSOD表达随年龄增长的增加成正比。这种增加先于运动神经元变性。与脑相比，脊髓中人类CuZnSOD表达水平更高，以及由此产生的自由基生成差异，为理解该疾病模型中脊髓的选择性易损性提供了基础。
