Role of mutant SOD1 disulfide oxidation and aggregation in the pathogenesis of familial ALS
Role of mutant SOD1 disulfide oxidation and aggregation in the pathogenesis of familial ALS
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DOI：
10.1073/pnas.0902505106
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发表时间：
2009-05-12
影响因子：
11.1
通讯作者：
Borchelt, David R.
中科院分区：
文献类型：
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作者：
Karch, Celeste M.;Prudencio, Mercedes;Borchelt, David R.
由超氧化物歧化酶（SOD） 1突变引起的家族性(f) ALS转基因小鼠出现瘫痪，其病理包括突变蛋白聚集形式的积累。使用高灵敏度的洗涤剂提取试验，我们追踪了SOD1在SOD1- fals小鼠（G93A， G37R和H46R/H48Q）整个疾病过程中洗涤剂不溶性和二硫交联SOD1聚集体的外观和丰度。我们证明，二硫交联的、洗涤剂不溶性的突变SOD1聚集体的积累主要发生在疾病的后期，同时出现快速进展的症状。我们没有发现异常的分子间二硫键在促进突变SOD1聚集中起重要作用的模型证据，相反，这种交联似乎是次要事件。此外，通过细胞培养和小鼠模型，我们发现缺乏正常分子内二硫键的突变蛋白是不溶性SOD1聚集体的主要组成部分。总的来说，我们的研究结果提示了一种模型，在这种模型中，可溶性形式的SOD1突变体引发疾病，其聚集量较大，仅涉及疾病最后阶段快速进展的事件。在疾病的最后阶段，突变SOD1中正常分子内二硫键的氧化异常促进突变蛋白的聚集。
Transgenic mice that model familial (f) ALS, caused by mutations in superoxide dismutase (SOD) 1, develop paralysis with pathology that includes the accumulation of aggregated forms of the mutant protein. Using a highly sensitive detergent extraction assay, we traced the appearance and abundance of detergent-insoluble and disulfide cross-linked aggregates of SOD1 throughout the disease course of SOD1-fALS mice (G93A, G37R, and H46R/H48Q). We demonstrate that the accumulation of disulfide cross-linked, detergent-insoluble, aggregates of mutant SOD1 occurs primarily in the later stages of the disease, concurrent with the appearance of rapidly progressing symptoms. We find no evidence for a model in which aberrant intermolecular disulfide bonding has an important role in promoting the aggregation of mutant SOD1, instead, such cross-linking appears to be a secondary event. Also, using both cell culture and mouse models, we find that mutant protein lacking the normal intramolecular disulfide bond is a major component of the insoluble SOD1 aggregates. Overall, our findings suggest a model in which soluble forms of mutant SOD1 initiate disease with larger aggregates implicated only in rapidly progressing events in the final stages of disease. Within the final stages of disease, abnormalities in the oxidation of a normal intramolecular disulfide bond in mutant SOD1 facilitate the aggregation of mutant protein.