Copper-zinc superoxide dismutase (SOD1) plays a protective role against oxidative stress. On the other hand, recent studies suggest that SOD1 itself is a major target of oxidative damage and has its own pathogenicity in various neurodegenerative diseases, including familial amyotrophic lateral sclerosis. Only human and great ape SOD1s among mammals have the highly reactive free cysteine residue, Cys 111 , at the surface of the SOD1 molecule. The purpose of this study was to investigate the role of Cys 111 in the oxidative damage of the SOD1 protein, by comparing the oxidative susceptibility of recombinant human SOD1 modified with 2-mercaptoethanol at Cys 111 (2-ME-SOD1) to wild-type SOD1. Wild-type SOD1 was more sensitive to oxidation by hydrogen peroxide-generating fragments, oligomers, and charge isomers compared with 2-ME-SOD1. Moreover, wild-type SOD1, but not 2-ME-SOD1, generated an upper shifted band in reducing SDS-PAGE even by air oxidation. Using mass spectrometry and limited proteolysis, this upper band was identified as an oxidized subunit of SOD1; the sulfhydryl group (Cys-SH) of Cys 111 was selectively oxidized to cysteine sulfinic acid (Cys-SO 2 H) and to cysteine sulfonic acid (Cys-SO 3 H). (2). Moreover, incubation with excess H 2 O 2 caused oxidation of almost all histidine and cysteine residues (3), fragmentation (4, 5) and aggregation (6, 7) of SOD1 itself. Co-incubation with bicarbonate and H 2 O 2 also induced bicarbonate radical anion formation, resulting in oligomerization of human SOD1 (8).The familial form of amyotrophic lateral sclerosis (ALS) is associated with specific mutations in the SOD1 gene (SOD1) that encodes 153 amino acids (9, 10). To date, more than 110 familial ALS (FALS)-causing mutations in SOD1 have been identified (available on the World Wide Web); however, the mechanism by which SOD1 mutants induce ALS remains unknown. The presence of intracellular aggregates that contain SOD1 in spinal cord motor neurons is thought to be a pathological hallmark of ALS. In particular, FALS-linked mutant SOD1s are prone to misfolding and aggregation (11,12). Recently, Ezzi et al. (7) reported that even wild-type SOD1 results in aggregation after oxidation, and the oxidized wildtype SOD1 gains properties like FALS mutant SOD1s. In addition to ALS, oxidative damaged SOD1 proteins were detected in the brains of patients with Alzheimer and Parkinson diseases (13). These findings suggest that oxidized SOD1 plays a role in the pathophysiology of various neurodegenerative diseases.

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Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic diseases, and results in the development of fibrosis. Oxidative stress is thought to be one of the underlying causes of NAFLD. Copper/zinc superoxide dismutase (SOD1) is a primary antioxidative enzyme that scavenges superoxide anion radicals. Although SOD1 knockout (KO) mice have been reported to develop fatty livers, it is not known whether this lack of SOD1 leads to the development of fibrosis. Since the accumulation of collagen typically precedes liver fibrosis, we assessed the balance between the synthesis and degradation of collagen in liver tissue from SOD1 KO mice. We found a higher accumulation of collagen in the livers of SOD1 KO mice compared to wild type mice. The level of expression of HSP47, a chaperone of collagen, and a tissue inhibitor (TIMP1) of matrix metalloproteinases (a collagen degradating enzyme) was also increased in SOD1 KO mice livers. These results indicate that collagen synthesis is increased but that its degradation is inhibited in SOD1 KO mice livers. Moreover, SOD1 KO mice liver sections were extensively modified by advanced glycation end products (AGEs), which suggest that collagen in SOD1 KO mice liver might be also modified with AGEs and then would be more resistant to the action of collagen degrading enzymes. These findings clearly show that oxidative stress plays an important role in the progression of liver fibrosis.