Structure analysis of mutant SOD1 and ALS immunotherapy using new monoclonal antibodies

虽然Cu， zn -超氧化物歧化酶（SOD1）基因突变是家族性肌萎缩性侧索硬化症（FALS）的病因之一，但其发病机制尚不清楚。由于突变型SOD1不稳定且容易聚集，因此其单克隆抗体（mab）的构象和反应性与野生型SOD1不同。在这项研究中，我们制作了各种新的单克隆抗体，以检测突变型SOD1与野生型SOD1之间的微小构象差异。部分单抗对不同SOD1突变表现出不同的反应性，并通过免疫组化分析在ALS模型小鼠脊髓中标记路易体样透明包涵体。因此，这些单克隆抗体将有助于检测SOD1的突变构象变化，并开发新的ALS免疫治疗方法。此外，我们确定了SOD1的晶体结构，这也将有助于确定SOD1- mab复合物的结构。

Although mutations of Cu,Zn-superoxide dismutase (SOD1) gene is one of causes of Familial Amyotrophic lateral sclerosis (FALS), the mechanism responsible for FALS remains unclear. Because mutant SOD1s are unstable and prone to aggregate, they would have different conformation and reactivity of monoclonal antibodies (mAbs) compared with wild-type SOD1. In this study, we made new various mAbs in order to detect tiny conformational differences between mutant SOD1s and wild-type SOD1. Some mAbs exhibited the different reactivity against the different mutation of SOD1 and labeled Lewy-body-like hyaline inclusions in the spinal cord of ALS model mice by immunohistochemical analysis. Therefore, these mAbs will be useful in detecting the conformational changes of SOD1 by mutation and developing a new ALS immunotherapy. In addition, we determined the crystal structure of SOD1, which will be also useful in determining the structure of SOD1-mAb complex.