Neurochemical Research 2009-11-01

New insights into mechanisms of gamma-diketone-induced axonopathy.

Desire Tshala-Katumbay, Paul Desjardins, Mohammad Sabri, Roger Butterworth, Peter Spencer

Index: Neurochem. Res. 34(11) , 1919-23, (2009)

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Abstract

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.