New Insights into Mechanisms of γ-Diketone-Induced Axonopathy
- 68 Downloads
We analyzed the impact of axonopathy-inducing agents 1,2-diacetylbenzene (1,2-DAB) and 2,5-hexanedione (2,5-HD) on membrane-bound protein disulfide isomerase (mPDI) versus soluble PDI (sPDI), or PDI-family member thioredoxin (THX), and asked whether changes in PDI/THX were associated with production of oxidative/nitrosative species in the Sprague–Dawley rat. We show that 1,2-DAB and 2,5-HD lower the abundance of sPDI and THX. However, the protein expression of mPDI is increased in 1,2-DAB axonopathy and neuroproteins became more S-nitrosylated. The abundance of heme oxygenase-1 (HO-1) and isoforms of nitric oxide synthase (neuronal, endothelial, and inducible NOS) remained unchanged suggesting that S-nitrosylation occured via increased mPDI-transnitrosylation and/or diminished THX-denitrosylation. The transcription of PDI and glucose regulated protein-78 (GRP-78) remained unchanged indicating that post-translational modifications, e.g. S-nitrosylation, mediate the pathogenesis of γ-diketone axonopathy. These findings open opportunities for new therapeutic testing (e.g., supplementation with denitrosylating THX) in γ-diketone-induced axonal disease.
Keywords1,2-Diacetylbenzene Giant axonopathy 2,5-Hexanedione Protein disulfide isomerase S-nitrosylation Thioredoxin
The technical expertise of Victor Monterroso (Department of Comparative Medicine, OHSU, Portland OR) is appreciated. Funding: National Institute of Health K01NS052183 and the Oregon Worker Benefit Fund.
- 13.Tshala-Katumbay D, Monterroso V, Kayton R, Lasarev M, Sabri M, Spencer P (2008) Probing mechanisms of axonopathy. Part I: protein targets of 1,2-diacetylbenzene, the neurotoxic metabolite of aromatic solvent 1,2-diethylbenzene. Toxicol Sci 105:134–141. doi: 10.1093/toxsci/kfn103 PubMedCrossRefGoogle Scholar
- 14.Tshala-Katumbay D, Monterroso V, Kayton R, Lasarev M, Sabri M, Spencer P (2009) Probing mechanisms of axonopathy. Part II: protein targets of 2,5-hexanedione, the neurotoxic metabolite of the aliphatic solvent n-hexane. Toxicol Sci 107:482–489. doi: 10.1093/toxsci/kfn241 PubMedCrossRefGoogle Scholar
- 24.Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 281:30152–30165. doi: 10.1074/jbc.M603393200 PubMedCrossRefGoogle Scholar