title: A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, Global Center of Education and Research for Chemical Biology of the Diseases, University of Tokyo, Hongo, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Kengo
authors.initials: K
authors.lastname: Homma
authors.forename: Namiko
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Hisae
authors.initials: H
authors.lastname: Kadowaki
authors.forename: Naomi
authors.initials: N
authors.lastname: Tsuburaya
authors.forename: Isao
authors.initials: I
authors.lastname: Naguro
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Jun
authors.initials: J
authors.lastname: Goto
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishitoh
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D016923:Cell Death; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D016895:Culture Media, Serum-Free; D008565:Membrane Proteins; C000606290:SOD1 protein, human; C530424:derlin-1 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1