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

Seiichi Nagano and Toshiyuki Araki

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/63160

#### **Abstract**

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86 Update on Amyotrophic Lateral Sclerosis

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.

**Keywords:** amyotrophic lateral sclerosis, Cu, Zn‐superoxide dismutase, cysteine resi‐ dues, oxidative stress, monomerized SOD1

#### **1. Introduction**

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons, which affects skeletal muscle strength of the whole body. About 10% of ALS cases are affected in a familial trait, 25–30% of which are caused by mutations of *Cu, Zn‐superoxide dismutase (SOD1)* gene [1]. Although many causative genes of ALS have been identified so far, *SOD1* is still the second frequent responsible gene for ALS next to *C9orf72* [2]. Since the identification of the gene in 1993, research emphasis for ALS has been placed on uncovering the pathogenic

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mechanism of motor neuronal death by the disease‐causing mutant SOD1. We review the recent concept of neuronal toxicity by mutant SOD1 in relation to the posttranslational modification of SOD1 at cysteine residues, especially at Cys111, which is closely related to its conformational change, in ALS pathogenesis.
