Department of Medical Biosciences, Clinical Chemistry, Umeå University, 901 85, Umeå, Sweden.
Neuromolecular Med. 2013 Mar;15(1):147-58. doi: 10.1007/s12017-012-8204-z. Epub 2012 Oct 18.
A common cause of amyotrophic lateral sclerosis is mutations in superoxide dismutase-1, which provoke the disease by an unknown mechanism. We have previously found that soluble hydrophobic misfolded mutant human superoxide dismutase-1 species are enriched in the vulnerable spinal cords of transgenic model mice. The levels were broadly inversely correlated with life spans, suggesting involvement in the pathogenesis. Here, we used methods based on antihuman superoxide dismutase-1 peptide antibodies specific for misfolded species to explore the composition and amounts of soluble misfolded human superoxide dismutase-1 in tissue extracts. Mice expressing 5 different human superoxide dismutase-1 variants with widely variable structural characteristics were examined. The levels were generally higher in spinal cords than in other tissues. The major portion of misfolded superoxide dismutase-1 was shown to be monomers lacking the C57-C146 disulfide bond with large hydrodynamic volume, indicating a severely disordered structure. The remainder of the misfolded protein appeared to be non-covalently associated in 130- and 250-kDa complexes. The malleable monomers should be prone to aggregate and associate with other cellular components, and should be easily translocated between compartments. They may be the primary cause of toxicity in superoxide dismutase-1-induced amyotrophic lateral sclerosis.
肌萎缩侧索硬化症的一个常见病因是超氧化物歧化酶-1 的突变，其未知机制引发了这种疾病。我们之前发现，可溶性疏水性错误折叠的突变型人超氧化物歧化酶-1 物种在转基因模型小鼠的易损脊髓中富集。水平与寿命广泛呈负相关，表明其参与了发病机制。在这里，我们使用了基于针对错误折叠物种的抗人超氧化物歧化酶-1 肽抗体的方法来探索组织提取物中可溶性错误折叠人超氧化物歧化酶-1 的组成和含量。研究了表达 5 种不同具有广泛结构特征的人超氧化物歧化酶-1 变体的小鼠。错误折叠的超氧化物歧化酶-1 的水平通常在脊髓中比在其他组织中更高。表明主要部分的错误折叠超氧化物歧化酶-1 是缺乏 C57-C146 二硫键的单体，具有大的流体力学体积，表明结构严重无序。错误折叠蛋白的其余部分似乎以 130-和 250-kDa 复合物的非共价形式存在。可塑单体应该容易聚集并与其他细胞成分结合，并且容易在隔室之间转移。它们可能是超氧化物歧化酶-1 诱导的肌萎缩侧索硬化症中毒性的主要原因。
