期刊
ANNALS OF NEUROLOGY
卷 72, 期 5, 页码 739-749出版社
WILEY
DOI: 10.1002/ana.23668
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [100360211, S 20229004]
- National Institute of Biomedical Innovation [0811]
- Tokyo Biochemical Research Foundation
- Takeda Science Foundation
- Uehara Memorial Foundation
- Suzuken Memorial Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Nakabayashi Trust for ALS Research
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Grants-in-Aid for Scientific Research [10J09619, 20229004, 22390347, 24659027, 23659033] Funding Source: KAKEN
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
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