New insights into mechanisms of gamma-diketone-induced axonopathy.
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 gamma-diketone axonopathy. These findings open opportunities for new therapeutic testing (e.g., supplementation with denitrosylating THX) in gamma-diketone-induced axonal disease.
Tshala-Katumbay
Desire
D
Department of Neurology, Portland, OR, USA. tshalad@ohsu.edu
Desjardins
Paul
P
Sabri
Mohammad
M
Butterworth
Roger
R
Spencer
Peter
P
D000098:Acetophenones; D000818:Animals; D001369:Axons / Q000473:pathology*; D002462:Cell Membrane / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006588:Hexanones; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013118:Spinal Cord Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D013879:Thioredoxins / Q000378:metabolism; D014158:Transcription, Genetic
D000098:Acetophenones; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D006588:Hexanones; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D009603:Nitroso Compounds; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013879:Thioredoxins; C048792:1,2-diacetylbenzene; C011269:2,5-hexanedione; D019001:Nitric Oxide Synthase; D051547:Heme Oxygenase-1; D019704:Protein Disulfide-Isomerases