Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models
Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models
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在小鼠 ALS 模型中，突变体超氧化物歧化酶 1 的可溶性错误折叠亚组分在整个生命过程中在脊髓中富集
DOI：
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发表时间：
2007
影响因子：
11.1
通讯作者：
S. Marklund
中科院分区：
文献类型：
--
作者：
P. Zetterström;H. Stewart;D. Bergemalm;P. Jonsson;K. Graffmo;P. Andersen;T. Brännström;M. Oliveberg;S. Marklund
超氧化物歧化酶-1（SOD 1）突变体通过一种未知的细胞毒性机制引起ALS。我们以前已经表明，稳定的SOD 1突变体D90 A和G93 A是丰富的，并显示在肝脏和肾脏中的转基因小鼠ALS模型的最高水平，而不稳定的G85 R和G127 X突变体是稀缺的，但在中枢神经系统中富集。这些数据表明，运动区富集的微量错误折叠的SOD 1可能发挥ALS引起的细胞毒性。开发了疏水相互作用色谱（HIC）方案，目的是测定体内组织中可溶性错误折叠SOD 1的丰度。大多数G85 R和G127 X突变体SOD 1在测定中结合，但只有D90 A和G93 A突变体的微小亚组分。然而，在这些模型中，与SOD 1结合的SOD 1的绝对水平是相似的，并且与寿命呈广泛的负相关。它们通常在易感脊髓中富集。结合SOD 1的二硫键还原亚基缺乏金属离子，也亚基，显然进行非天然intrasubunit二硫键。从出生到死亡的水平都很高，与在终末阶段聚集在一起的SOD 1的量相当。结合SOD 1的物质的大小从单体到三聚体不等。这些物种在具有广泛不同分子特征的SOD 1突变体中形成最小公分母，并且可能参与导致ALS的细胞毒性。
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 chromatography (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.
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DOI：
10.1073/pnas.0602048103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Furukawa, Y;Fu, RG;O'Halloran, TV
通讯作者：
O'Halloran, TV
影响因子：
56.9
作者：
Bruijn, LI;Houseweart, MK;Cleveland, DW
通讯作者：
Cleveland, DW
影响因子：
56.9
作者：
Estévez, AG;Crow, JP;Beckman, JS
通讯作者：
Beckman, JS
DOI：
10.1073/pnas.93.11.5472
发表时间：
1996-05-28
影响因子：
11.1
作者：
Mourelatos, Z;Gonatas, NK;DalCanto, MC
通讯作者：
DalCanto, MC