title: S-nitrosylated protein disulfide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Xueping
authors.initials: X
authors.lastname: Chen
authors.forename: Xiaosha
authors.initials: X
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Teng
authors.initials: T
authors.lastname: Guan
authors.forename: Huifang
authors.initials: H
authors.lastname: Shang
authors.forename: Liying
authors.initials: L
authors.lastname: Cui
authors.forename: Xin-Min
authors.initials: XM
authors.lastname: Li
authors.forename: Jiming
authors.initials: J
authors.lastname: Kong
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001710:Biotin / Q000378:metabolism; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding / Q000187:drug effects; D026403:S-Nitrosothiols; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: D026403:S-Nitrosothiols; D009569:Nitric Oxide; D001710:Biotin; C021315:S-nitrosocysteine; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D019704:Protein Disulfide-Isomerases; D003545:Cysteine