Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis
Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis
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DOI：
10.1074/jbc.m802083200
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发表时间：
2008-08-29
影响因子：
4.8
通讯作者：
Nukina, Nobuyuki
中科院分区：
文献类型：
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作者：
Furukawa, Yoshiaki;Kaneko, Kumi;Nukina, Nobuyuki
铜锌超氧化物歧化酶（SOD 1）的显性突变导致肌萎缩侧索硬化症（fALS）的家族性形式，并且已提出突变SOD 1的聚集在神经变性中起作用。越来越多的证据表明，fALS引起的突变使SOD1的天然结构不稳定，导致异常的蛋白质相互作用聚集。SOD1在铜和锌结合和分子内二硫键形成后变得稳定并具有酶活性，但仍不清楚SOD1成熟过程中的哪个步骤在病理性聚集中是重要的。在这项研究中，我们已经表明，apoSOD 1没有二硫化物是最容易的状态，形成淀粉样纤维状聚集体。fALS突变损害锌结合、二硫键形成或两者，导致聚集倾向、载脂蛋白和二硫键还原的SOD 1积累。此外，我们已经发现，铜分子伴侣SOD1（CCS）促进SOD1的成熟和CCS过表达改善突变体SOD1在体内的细胞内聚集。基于我们在体内和体外的结果，我们建议，促进翻译后修饰是一个有前途的策略，以减少SOD1聚集在细胞中。
Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (fALS), and aggregation of mutant SOD1 has been proposed to play a role in neurodegeneration. A growing body of evidence suggests that fALS-causing mutations destabilize the native structure of SOD1, leading to aberrant protein interactions for aggregation. SOD1 becomes stabilized and enzymatically active after copper and zinc binding and intramolecular disulfide formation, but it remains unknown which step(s) in the SOD1 maturation process is important in the pathological aggregation. In this study we have shown that apoSOD1 without disulfide is the most facile state for formation of amyloid-like fibrillar aggregates. fALS mutations impair either zinc binding, disulfide formation, or both, leading to accumulation of the aggregation-prone, apo, and disulfide-reduced SOD1. Moreover, we have found that the copper chaperone for SOD1 (CCS) facilitates maturation of SOD1 and that CCS overexpression ameliorates intracellular aggregation of mutant SOD1 in vivo. Based on our in vivo and in vitro results, we propose that facilitation of post-translational modifications is a promising strategy to reduce SOD1 aggregation in the cell.