Monomerized Cu,Zn-superoxide dismutase induces oxidative stress through aberrant Cu binding

Abstract

Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS). Lowering intracellular Cu improves the FALS-like phenotype of mutant SOD1 mice. Using immobilized Cu-affinity chromatography, we have previously shown that mutant SOD1 is expressed as two affinity fractions, one with high affinity for Cu (SOD1HAC) and one with low affinity (SOD1LAC), whereas wild-type SOD1 is expressed only as SOD1LAC. Here we further characterize SOD1HAC to ascertain the toxicity of mutant SOD1 species. We found that SOD1HAC was modified at cysteine residues (Cys) and could be generated from wild-type SOD1 by oxidation of Cys. SOD1HAC mainly consisted of monomer, whe..