**1. Introduction**

300 Amyotrophic Lateral Sclerosis

Williamson, J., Goldman, J. and Marder, K. S. (2009). "Genetic aspects of Alzheimer disease."

Wyttenbach, A., Carmichael, J., Swartz, J., Furlong, R. A., Narain, Y., Rankin, J. and

Zetterstrom, P., Stewart, H. G., Bergemalm, D., Jonsson, P. A., Graffmo, K. S., Andersen, P.

disease." *Proc Natl Acad Sci U S A* 97(6): 2898-903.

Rubinsztein, D. C. (2000). "Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's

M., Brannstrom, T., Oliveberg, M. and Marklund, S. L. (2007). "Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models." *Proc Natl Acad Sci U S A* 104(35): 14157-62.

*Neurologist* 15(2): 80-6.

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons. About 10 % of ALS cases are affected in a familial trait, a subset of which is caused by the mutation of *Cu, Zn-superoxide dismutase (SOD1)* gene (Rosen et al., 1993). Since the identification of the gene for familial ALS, research emphasis for ALS has been placed on uncovering the pathogenic mechanism of motor neuronal death by the disease-causing mutant SOD1. So far over 150 different mutations of *SOD1* gene have been found in familial ALS patients, and they are scattered throughout the entire sequence of the gene regardless of specific functional domains. Transgenic mice that express mutant SOD1, but not wild type SOD1 nor SOD1 knockout mice, develop motor neuron disease, often while retaining normal dismutase activity (Gurney et al., 1994; Reaume et al., 1996). It means that mutant SOD1 gains a new aberrant toxic function apart from the primary enzymatic function of the protein, which has remained uncertain to date. Although the nature of mutant SOD1 toxicity has not been fully determined, conformational abnormalities of mutant SOD1 protein are deeply involved in the pathogenesis of familial ALS (Chattopadhyay & Valentine, 2009). Moreover, recent studies suggest that the phenotype of sporadic ALS also might be regulated by the conformational change of wild type SOD1 (Bosco et al., 2010). I review the recent concept of neuronal toxicity by oxidatively-modified SOD1, which is closely related to its conformational change, in ALS pathogenesis.
