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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria
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Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria

机译：转化为肌萎缩性侧索硬化症的表型与线粒体中SOD1的分子间连锁不溶性聚集有关

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摘要

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.
机译：肌萎缩性侧索硬化症（ALS）家族形式的20％是由于获得毒性功能而导致的铜，锌超氧化物歧化酶基因（SOD1）突变引起的。突变体SOD1的这种毒性功能的性质仍然未知。在这里，我们显示野生型SOD1不仅加速了ALS表型的发作，而且还可以在突变的SOD1转基因小鼠模型中将未受影响的表型转化为AILS表型。对单转基因和双转基因小鼠的进一步分析表明，突变型SOD1从可溶形式转化为聚集和去污剂不溶形式与转基因小鼠中ALS表型的发展有关。 WT SOD1从可溶形式向聚集和不可溶形式的转化还与疾病的恶化或在双转基因小鼠中转化为疾病表型有关。在脊髓线粒体部分观察到这种转化涉及形成不溶性SOD1二聚体和多聚体，它们通过分子间二硫键通过SOD1中的半胱氨酸残基的氧化而交联。因此，我们的数据显示了一种分子机制，通过该机制，氧化还原过程将SOD1（一种在细胞中防御自由基的重要蛋白质）转化为聚集的，显然与ALS相关的有毒二聚体和多聚体。这些发现提供了氧化，蛋白质聚集，线粒体损伤和SOD1介导的ALS之间的直接联系的证据，并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，现在可以开发和测试基于这些观察结果的合理疗法。

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