| First Author | Chen X | Year | 2013 |
| Journal | J Neurochem | Volume | 124 |
| Issue | 1 | Pages | 45-58 |
| PubMed ID | 23043510 | Mgi Jnum | J:191002 |
| Mgi Id | MGI:5451142 | Doi | 10.1111/jnc.12046 |
| Citation | Chen X, et al. (2013) S-nitrosylated protein disulfide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis. J Neurochem 124(1):45-58 |
| abstractText | A major hallmark of mutant superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis is SOD1-immunopositive inclusions found within motor neurons. The mechanism by which SOD1 becomes aggregated, however, remains unclear. In this study, we aimed to investigate the role of nitrosative stress and S-nitrosylation of protein disulfide isomerase (PDI) in the formation of SOD1 aggregates. Our data show that with disease progression inducible nitric oxide synthase (iNOS) was up-regulated, which generated high levels of nitric oxide (NO) and subsequently induced S-nitrosylation of PDI in the spinal cord of mutant SOD1 transgenic mice. This was further confirmed by in vitro observation that treating SH-SY5Y cells with NO donor S-nitrosocysteine triggered a dose-dependent formation of S-nitrosylated PDI. When mutant SOD1 was over-expressed in SH-SY5Y cells, the iNOS expression was up-regulated, and NO generation was consequently increased. Furthermore, both S-nitrosylation of PDI and the formation of mutant SOD1 aggregates were detected in the cells expressing mutant SOD1(G93A) . Blocking NO generation with the NOS inhibitor N-nitro-l-arginine attenuated the S-nitrosylation of PDI and inhibited the formation of mutant SOD1 aggregates. We conclude that NO-mediated S-nitrosylation of PDI is a contributing factor to the accumulation of mutant SOD1 aggregates in amyotrophic lateral sclerosis. |
