Premium
A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis‐linked SOD1 mutants
Author(s) -
Fujisawa Takao,
Homma Kengo,
Yamaguchi Namiko,
Kadowaki Hisae,
Tsuburaya Naomi,
Naguro Isao,
Matsuzawa Atsushi,
Takeda Kohsuke,
Takahashi Yuji,
Goto Jun,
Tsuji Shoji,
Nishitoh Hideki,
Ichijo Hidenori
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23668
Subject(s) - sod1 , amyotrophic lateral sclerosis , mutant , endoplasmic reticulum , monoclonal antibody , mutation , superoxide dismutase , antibody , wild type , biology , chemistry , microbiology and biotechnology , immunology , genetics , biochemistry , medicine , gene , oxidative stress , disease , pathology
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. ANN NEUROL 2012;72:739–749