An examination of wild-type SOD1 in modulating the toxicity and aggregation of ALS-associated mutant SOD1
An examination of wild-type SOD1 in modulating the toxicity and aggregation of ALS-associated mutant SOD1
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DOI：
10.1093/hmg/ddq408
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发表时间：
2010-12-15
影响因子：
3.5
通讯作者：
Borchelt, David R.
中科院分区：
文献类型：
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作者：
Prudencio, Mercedes;Durazo, Armando;Borchelt, David R.
超氧化物歧化酶 1 (SOD1) 突变与肌萎缩侧索硬化症 (fALS) 家族病例相关。对转基因小鼠的研究表明，野生型 (WT) SOD1 可以调节突变型 SOD1 的毒性。在本研究中，我们证明 WT SOD1 对表达突变型人类 SOD1 (hSOD1) 的转基因小鼠出现瘫痪的年龄的影响受到 ALS 突变的性质和 WT hSOD1 表达水平的影响。我们发现，无论 WT SOD1 是否改变病程，WT 和突变型 hSOD1 在表达这两种蛋白的有症状小鼠中均以洗涤剂不溶性聚集物的形式积累。然而，在突变体 SOD1 聚集的细胞模型中使用一组荧光标记的 SOD1 变体，我们证明突变体和 WT SOD1 在聚集体形成中的相互作用不仅仅是突变体和 WT 蛋白的共组装。总的来说，这些数据表明，fALS 中正常 SOD1 等位基因的产物有可能影响突变 SOD1 的毒性，并且与突变蛋白的复杂相互作用可能会影响突变 SOD1 产生的聚集体和包涵体的形成。
Mutations in superoxide dismutase 1 (SOD1) are associated with familial cases of amyotrophic lateral sclerosis (fALS). Studies in transgenic mice have suggested that wild-type (WT) SOD1 can modulate the toxicity of mutant SOD1. In the present study, we demonstrate that the effects of WT SOD1 on the age at which transgenic mice expressing mutant human SOD1 (hSOD1) develop paralysis are influenced by the nature of the ALS mutation and the expression levels of WT hSOD1. We show that regardless of whether WT SOD1 changes the course of disease, both WT and mutant hSOD1 accumulate as detergent-insoluble aggregates in symptomatic mice expressing both proteins. However, using a panel of fluorescently tagged variants of SOD1 in a cell model of mutant SOD1 aggregation, we demonstrate that the interactions between mutant and WT SOD1 in aggregate formation are not simply a co-assembly of mutant and WT proteins. Overall, these data demonstrate that the product of the normal SOD1 allele in fALS has potential to influence the toxicity of mutant SOD1 and that complex interactions with the mutant protein may influence the formation of aggregates and inclusion bodies generated by mutant SOD1.