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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models
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Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models

机译：突变型超氧化物歧化酶-1s的可溶性错折叠亚部分在鼠ALS模型的整个生命中都富集在脊髓中

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Mutants of superoxide dismutase-1 (SOD1) cause ALS by an unidentified cytotoxic mechanism. We have previously shown that the stable SOD1 mutants D90A and G93A are abundant and show the highest levels in liver and kidney in transgenic murine ALS models, whereas the unstable G85R and G127X mutants are scarce but enriched in the CNS. These data indicated that minute amounts of misfolded SOD1 enriched in the motor areas might exert the ALS-causing cytotoxicity. A hydrophobic interaction chromatogra-phy (HIC) protocol was developed with the aim to determine the abundance of soluble misfolded SOD1 in tissues in vivo. Most G85R and G127X mutant SOD1s bound in the assay, but only minute subfractions of the D90A and G93A mutants. The absolute levels of HIC-binding SOD1 were, however, similar and broadly inversely related to lifespans in the models. They were generally enriched in the susceptible spinal cord. The HIC-binding SOD1 was composed of disulfide-reduced subunits lacking metal ions and also subunits that apparently carried nonnative intrasubunit disulfide bonds. The levels were high from birth until death and were comparable to the amounts of SOD1 that become sequestered in aggregates in the terminal stage. The HIC-binding SOD1 species ranged from monomeric to trimeric in size. These species form a least common denominator amongst SOD1 mutants with widely different molecular characteristics and might be involved in the cytotoxicity that causes ALS.
机译：超氧化物歧化酶-1（SOD1）的突变体通过未知的细胞毒性机制引起ALS。我们先前已经证明，在转基因鼠ALS模型中，稳定的SOD1突变体D90A和G93A丰富，并且在肝脏和肾脏中显示最高水平，而不稳定的G85R和G127X突变体却很少，但富含CNS。这些数据表明，在运动区富集的微量错误折叠的SOD1可能发挥ALS的细胞毒性作用。为了确定体内组织中可溶性错误折叠的SOD1的丰度，开发了疏水相互作用色谱（HIC）方案。大多数G85R和G127X突变体SOD1s结合在测定中，但D90A和G93A突变体只有微小的亚组分。但是，与HIC结合的SOD1的绝对水平与模型的寿命相似且大致成反比。它们通常富含易感脊髓。结合HIC的SOD1由缺乏金属离子的二硫化物还原的亚基以及显然带有非天然亚单位内二硫键的亚基组成。从出生到死亡，其水平都很高，与末期聚集在聚集体中的SOD1的含量相当。结合HIC的SOD1分子的大小从单体到三聚体不等。这些物种在分子特征差异很大的SOD1突变体中形成了最不常见的分母，并且可能参与导致ALS的细胞毒性。

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