A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants
A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants
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DOI：
10.1002/ana.23668
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发表时间：
2012-11-01
影响因子：
11.2
通讯作者：
Ichijo, Hidenori
中科院分区：
文献类型：
--
作者：
Fujisawa, Takao;Homma, Kengo;Ichijo, Hidenori
目的：肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以上、下运动神经元选择性丧失为特征的神经退行性疾病。尽管在ALS患者中已经鉴定了超过100种不同的Cu，Zn超氧化物歧化酶（SOD 1）突变，但它们是否都是致病突变仍然存在争议。因此，有必要对SOD 1突变引起的ALS进行分子机制诊断和治疗。研究方法：我们以前报道过3种致病的SOD 1突变通过诱导SOD 1与ER稳态机制的一个组成部分Derlin-1结合而引起慢性内质网应激。在这里，我们系统地分析了132 SOD 1突变体，发现大多数有一个组成性暴露的Derlin-1结合区（DBR），封闭在野生型蛋白。为了开发能够特异性识别毒性SOD 1突变体异常结构的新型分子机制抗体，我们制备了抗DBR的单克隆抗体。结果如下：针对DBR产生的单克隆抗体MS 785将大多数ALS致病性SOD 1突变体与野生型和无毒突变体区分开来。此外，MS 785识别来自14名携带SOD 1突变的ALS患者的B淋巴细胞中的内源性SOD 1，但不识别来自11名健康对照的内源性SOD 1。解释：这是第一项研究，以解决所有ALS致病SOD 1突变体的共同属性。MS 785是第一个基于分子机制的抗体，它被证明能够区分ALS相关的毒性SOD 1突变体与野生型和无毒突变体。因此，MS 785可能成为诊断ALS的创新工具。神经网络2012;72：739749
Objective: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by the selective loss of upper and lower motoneurons. Although >100 different Cu, Zn superoxide dismutase (SOD1) mutations have been identified in ALS patients, it remains controversial whether all of them are disease-causative mutations. Therefore, it is necessary to develop molecular mechanism-based diagnosis and treatment of ALS caused by SOD1 mutations. Methods: We previously reported that 3 pathogenic mutations of SOD1 cause chronic endoplasmic reticulum (ER) stress by inducing the binding of SOD1 to Derlin-1, a component of the ER homeostatic machinery. Here, we systematically analyzed 132 SOD1 mutants and found that most have a constitutively exposed Derlin-1binding region (DBR) that is occluded in the wild-type protein. To develop the novel molecular mechanism-based antibody that can specifically recognize the aberrant structure of toxic SOD1 mutants, we generated the monoclonal antibody against the DBR. Results: MS785, a monoclonal antibody generated against the DBR, distinguished most ALS-causative SOD1 mutants from both wild-type and nontoxic mutants. Moreover, MS785 recognized endogenous SOD1 in B lymphocytes derived from 14 ALS patients carrying SOD1 mutations but not from 11 healthy controls. Interpretation: This is the first study to address the common property of all ALS-causative SOD1 mutants. MS785 is the first molecular mechanism-based antibody that was shown to be able to distinguish ALS-linked toxic SOD1 mutants from both wild-type and nontoxic mutants. MS785 may thus become an innovative tool for the diagnosis of ALS. ANN NEUROL 2012;72:739749