Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: Its modulation by the proteasome and Hsp70
Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: Its modulation by the proteasome and Hsp70
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DOI：
10.1016/j.bbrc.2006.02.170
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发表时间：
2006-05-12
影响因子：
3.1
通讯作者：
Kato, T
中科院分区：
文献类型：
--
作者：
Koyama, S;Arawaka, S;Kato, T
在家族性肌萎缩侧索硬化症（fALS）的一个亚组患者中，发生了错误折叠的Cu/Zn超氧化物歧化酶（SOD 1）的蓄积。为了鉴定SOD 1从正常可溶形式到不溶性聚集体的转化，我们研究了fALS连接的H46 R SOD 1转基因小鼠中SOD 1溶解度随衰老的变化。突变体SOD 1特异性地改变为不溶性形式，其依次分离成Triton X-100不溶性/十二烷基硫酸钠（SDS）可溶性和SDS不溶性/甲酸可溶性物质。在脊髓中，SDS-可解离的可溶性SOD 1单体和SDS-稳定的可溶性二聚体的水平在运动功能障碍发作之前显著升高。在COS-7细胞表达H46 R SOD 1，与蛋白酶体抑制剂的治疗重演的SOD 1的溶解度在转基因小鼠的改变。与此相反，Hsp 70的过度表达减少积累的muplant特异性不溶性SOD 1。SDS可溶性低分子量的H46 R SOD 1的物种可能出现早期错误折叠的中间体时，他们的浓度超过了蛋白酶体和分子伴侣的能力。(c)2006年爱思唯尔公司All rights reserved.
Accumulation of misfolded Cu/Zn Superoxide dismutase (SOD1) occurs in patients with a subgroup of familial amyotrophic lateral sclerosis (fALS). To identify the conversion of SOD1 from a normally soluble form to insoluble aggregates, we investigated the change of SOD1 solubility with aging in fALS-linked H46R SOD1 transgenic mice. Mutant SOD1 specifically altered to insoluble forms, which were sequentially separated into Triton X-100-insoluble/sodium dodecyl Sulfate (SDS)-soluble and SDS-insoluble/formic acid-soluble species. In spinal cords, the levels of SDS-dissociable soluble SOD1 monomers and SDS-stable soluble dimers were significantly elevated before motor dysfunction onset. In COS-7 cells expressing H46R SOD1, treatment with proteasome inhibitors recapitulated the alteration of SOD1 solubility in transgenic mice. In contrast, overexpression of Hsp70 reduced accumulation of mutant-specific insoluble SOD1. SDS-soluble low molecular weight species of H46R SOD1 may appear as early misfolded intermediates when their concentration exceeds the capacity of the proteasome and molecular chaperones. (c) 2006 Elsevier Inc. All rights reserved.