Role of Cysteine Residue of Mutant Cu, Zn‐Superoxide Dismutase (SOD1) in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS)

Mutations of Cu, Zn‐superoxide dismutase (SOD1) gene have been identified in a subset of familial amyotrophic lateral sclerosis (ALS). Conformational change, that is, misfolding, of mutant SOD1 underlies its toxic gain of function for motor neuronal degeneration. Mutant SOD1 is prone to cause oxidative stress through the copper exposed on the protein by misfolding. The protein structure of SOD1 is critically affected by the redox state of cysteine residues, especially of Cys111. Oxidative modification of Cys111, which is enhanced in mutant SOD1, causes destabilization of the dimer interface to promote misfolding and aggregation of the protein. Substitution of Cys111 to serine alleviated the degeneration of motor neurons as well as the misfolding and aggregate formation of mutant SOD1 in the spinal cord of transgenic mice. It indicates that Cys111 is a crucial residue for the pathogenesis of ALS by mutant SOD1.