Expression of human FALS SOD in motorneurons of Drosophila
Expression of human FALS SOD in motorneurons of Drosophila
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DOI：
10.1016/s0891-5849(98)00333-5
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发表时间：
1999-05-01
影响因子：
7.4
通讯作者：
Hilliker, AJ
中科院分区：
文献类型：
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作者：
Elia, AJ;Parkes, TL;Hilliker, AJ
人类铜锌超氧化物歧化酶（SOD）的突变与家族性肌萎缩侧索硬化症（FALS）有关。虽然导致许多实验进展，这一发现还没有导致一个明确的理解的生化机制，其中突变的SOD促进运动神经元的退化，导致这种无法治愈的麻痹性疾病。为了探索FALS SOD介导的神经发病机制的生化机制，我们使用转基因方法将人类FALS SOD的表达靶向果蝇的运动神经元，果蝇是一种以其对SOD基因操作的表型敏感性而闻名的生物体。早些时候，我们发现在果蝇的运动神经元中靶向表达人SOD会导致成年寿命的显著延长（>40%），并挽救了大多数SOD无效突变体的表型。使用相同的通用系统，我们现在灰，如果有针对性地表达与FALS相关的人类SOD的突变等位基因导致瘫痪和过早死亡，或者在果蝇中是有害的，因为它是在人类和转基因小鼠。在这里，我们报告说，高水平表达的人类FALS SOD在运动神经元是无害的，并不促进瘫痪和过早死亡时，表达在果蝇的运动神经元。与此形成鲜明对比的是，在果蝇中表达的FALS SOD实际上延长寿命，增强抗氧化应激和部分救援SOD无效突变体的方式预测我们早期的研究野生型人SOD在果蝇运动神经元的表达。(C)1999 Elsevier Science Inc.
Mutations in human CuZn superoxide dismutase (SOD) have been associated with familial amyotrophic lateral sclerosis (FALS). Although leading to many experimental advances, this finding has not yet led to a clear understanding of the biochemical mechanism by which mutations in SOD promote the degeneration of motorneurons that causes this incurable paralytic disease. To explore the biochemical mechanism of FALS SOD-mediated neuropathogenesis, we used transgenic methodology to target the expression of a human FALS SOD to motorneurons of Drosophila, an organism known for its: phenotypic sensitivity to genetic manipulation of SOD. Earlier, we showed that targeted expression of human SOD in motorneurons of Drosophila causes a dramatic extension of adult lifespan (>40%) and rescues most of the phenotypes of SOD-null mutants. Using the same generic system, we now ash if targeted expression of a mutant allele of human SOD that is associated with FALS causes paralysis and premature death, or is otherwise injurious in Drosophila as it is in humans and transgenic mice. Here we report that high-level expression of a human FALS SOD in motorneurons is not detrimental and does not promote paralysis and premature death when expressed in motorneurons of Drosophila. In sharp contrast, the expression of FALS SOD in Drosophila actually extends lifespan, augments resistance to oxidative stress and partially rescues SOD-null mutants in a manner predicted by our earlier studies on the expression of wildtype human SOD in Drosophila motorneurons. (C) 1999 Elsevier Science Inc.