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

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.

journal_name

Neurochem Res

journal_title

Neurochemical research

authors

Tshala-Katumbay D,Desjardins P,Sabri M,Butterworth R,Spencer P

doi

10.1007/s11064-009-9977-9

subject

Has Abstract

pub_date

2009-11-01 00:00:00

pages

1919-23

issue

11

eissn

0364-3190

issn

1573-6903

journal_volume

34

pub_type

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