**7. Role of cysteine-oxidized wild type SOD1 in sporadic ALS**

In sporadic ALS, there had been no direct evidence that SOD1 was involved in the pathogenesis of the disease, except that some mutations of *SOD1* gene expressed familial ALS in a low penetration rate with seemingly 'sporadic' cases. The link between SOD1 and sporadic ALS was first introduced by the detection of SOD1 specifically modifiable with a chemical compound commonly in familial and sporadic ALS, although the molecular basis for it has not been determined in detail (Gruzman et al., 2007). It indicates that a similar conformational change in mutant and wild type SOD1 can trigger the phenotype of familial and sporadic ALS in common. In *in vitro* study, wild type SOD1 acquires toxic properties of mutant SOD1 through oxidation by hydrogen peroxide (Ezzi et al., 2007), implying that cysteine-oxidized wild type SOD1 may be a contributor to motor neuronal death in sporadic ALS.

Recently, a conformation-specific antibody generated against misfolded mutant SOD1 has been shown to recognize wild type SOD1 only when the protein was sulfonylated (-SO3H) at Cys111, and the antibody immunostained motor neurons in the spinal cords of sporadic ALS patients, but not of SOD1-unrelated familial ALS patients or controls (Bosco et al., 2010). Chemically oxidized or purified wild type SOD1 from sporadic ALS spinal cords inhibited kinesin-based fast axonal transport as did mutant SOD1, supposing that Cys111 mediated conformational change or misfolding of SOD1 is a shared pathological denominator of familial and sporadic ALS. Interestingly, most of the sporadic ALS-derived toxic SOD1 was soluble and non-aggregated, meaning that misfolding or monomerization is sufficient for SOD1 to gain the toxic property such as oxidative insult we have shown in mutant and wild type SOD1 (Kishigami et al., 2010). Further studies *in vivo* will be required to clarify the detailed mechanism of SOD1 toxicity mediated by oxidation of cysteine residues including Cys111.
