A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants

Ann Neurol. 2012 Nov;72(5):739-49. doi: 10.1002/ana.23668.


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-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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / immunology*
  • Animals
  • Antibodies, Monoclonal / metabolism*
  • Cell Death
  • Cells, Cultured
  • Culture Media, Serum-Free / pharmacology
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Humans
  • Immunoprecipitation
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Motor Neurons / pathology
  • Motor Neurons / physiology*
  • Mutation / genetics
  • Protein Binding / genetics
  • Protein Conformation
  • Spinal Cord / pathology
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1
  • Transfection


  • Antibodies, Monoclonal
  • Culture Media, Serum-Free
  • Membrane Proteins
  • SOD1 protein, human
  • derlin-1 protein, mouse
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1