Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria
Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria
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DOI：
10.1073/pnas.0602046103
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发表时间：
2006-05-02
影响因子：
11.1
通讯作者：
Siddique, T
中科院分区：
文献类型：
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作者：
Deng, HX;Shi, Y;Siddique, T
20%的肌萎缩性侧索硬化症（ALS）的家族形式是由铜，锌-超氧化物歧化酶基因（SOD 1）突变通过获得毒性功能引起的。突变SOD 1的这种毒性功能的性质在很大程度上仍然未知。在这里，我们表明WT SOD 1不仅加速ALS表型的发生，而且还可以在突变SOD 1转基因小鼠模型中将未受影响的表型转化为AILS表型。对单转基因小鼠和双转基因小鼠的进一步分析表明，突变体SOD 1从可溶性形式转化为聚集的和洗涤剂不溶性形式与转基因小鼠中ALS表型的发展相关。WT SOD 1从可溶形式转化为聚集和不溶性形式也与双转基因小鼠中疾病的恶化或转化为疾病表型相关。在脊髓的线粒体部分中观察到的这种转化涉及不溶性SOD 1二聚体和多聚体的形成，这些二聚体和多聚体通过SOD 1中半胱氨酸残基的氧化通过分子间二硫键交联。因此，我们的数据显示了一种分子机制，SOD 1，一种重要的蛋白质在细胞防御自由基，被转换为聚集的和明显的ALS相关的有毒二聚体和多聚体的氧化还原过程。这些发现提供了氧化，蛋白质聚集，线粒体损伤和SOD 1介导的ALS之间直接联系的证据，可能应用于衰老过程和其他迟发性神经退行性疾病。重要的是，基于这些观察的合理治疗现在可以开发和测试。
Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an AILS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single- and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.