S-nitrosylated protein disulfide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis
Article first published online: 1 NOV 2012
© 2012 International Society for Neurochemistry
Journal of Neurochemistry
Volume 124, Issue 1, pages 45–58, January 2013
How to Cite
J. Neurochem. (2013) 124, 45–58.
- Issue published online: 6 DEC 2012
- Article first published online: 1 NOV 2012
- Accepted manuscript online: 8 OCT 2012 12:12PM EST
- Manuscript Accepted: 24 SEP 2012
- Manuscript Revised: 23 SEP 2012
- Manuscript Received: 11 MAY 2012
- nitrosative stress;
- protein disulfide isomerase;
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 SOD1G93A. 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.