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

尽管铜锌超氧化物歧化酶(SOD1)基因突变是家族性肌萎缩侧索硬化症(FALS)的病因之一，但其发病机制尚不清楚。由于突变型SOD1s的不稳定性和聚集性，与野生型SOD1s相比，它们具有不同的单抗构象和反应性。在本研究中，我们制备了新的各种单抗，以检测突变型SOD1s和野生型SOD1s之间的微小构象差异。免疫组织化学分析显示，部分单抗对SOD1的不同突变表现出不同的反应性，并标记ALS模型小鼠脊髓内的路易体样透明包涵体。因此，这些单抗将有助于检测SOD1基因突变后的构象变化，为开发新的ALS免疫治疗方法奠定基础。此外，我们还测定了SOD_1的晶体结构，这也将有助于确定SOD_1-mAb络合物的结构。

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.