Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
Hum Mol Genet. 2010 Dec 15;19(24):4774-89. doi: 10.1093/hmg/ddq408. Epub 2010 Sep 24.
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.
超氧化物歧化酶 1（SOD1）中的突变与家族性肌萎缩侧索硬化症（fALS）有关。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，我们证明了 WT SOD1 对表达突变型人 SOD1（hSOD1）的转基因小鼠出现瘫痪的年龄的影响取决于 ALS 突变的性质和 WT hSOD1 的表达水平。我们表明，无论 WT SOD1 是否改变疾病进程，在表达两种蛋白的症状小鼠中，WT 和突变型 hSOD1 都作为去污剂不溶性聚集体积累。然而，使用突变型 SOD1 聚集的细胞模型中的一组荧光标记的 SOD1 变体，我们证明了聚集体形成中突变型和 WT SOD1 之间的相互作用不仅仅是突变型和 WT 蛋白的共组装。总体而言，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型 SOD1 的毒性，并且与突变蛋白的复杂相互作用可能影响突变型 SOD1 产生的聚集体和包含体的形成。
