A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants
Version of Record online: 21 AUG 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 5, pages 739–749, November 2012
How to Cite
Fujisawa, T., Homma, K., Yamaguchi, N., Kadowaki, H., Tsuburaya, N., Naguro, I., Matsuzawa, A., Takeda, K., Takahashi, Y., Goto, J., Tsuji, S., Nishitoh, H. and Ichijo, H. (2012), A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. Ann Neurol., 72: 739–749. doi: 10.1002/ana.23668
- Issue online: 27 DEC 2012
- Version of Record online: 21 AUG 2012
- Accepted manuscript online: 12 JUN 2012 12:19PM EST
- Manuscript Accepted: 4 MAY 2012
- Manuscript Revised: 29 APR 2012
- Manuscript Received: 31 JAN 2012
- Ministry of Education, Culture, Sports, Science, and Technology of Japan. Grant Numbers: 100360211, S 20229004
- Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation. Grant Number: 08-11
- 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
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.
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-1–binding 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.
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.
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;72:739–749