TY - JOUR
T1 - New insights into mechanisms of γ-Diketone-induced axonopathy
AU - Tshala-Katumbay, Desire
AU - Desjardins, Paul
AU - Sabri, Mohammad
AU - Butterworth, Roger
AU - Spencer, Peter
N1 - Funding Information:
Acknowledgments 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.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - 1,2-Diacetylbenzene
KW - 2,5-Hexanedione
KW - Giant axonopathy
KW - Protein disulfide isomerase
KW - S-nitrosylation
KW - Thioredoxin
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U2 - 10.1007/s11064-009-9977-9
DO - 10.1007/s11064-009-9977-9
M3 - Article
C2 - 19404740
AN - SCOPUS:70349586634
SN - 0364-3190
VL - 34
SP - 1919
EP - 1923
JO - Neurochemical Research
JF - Neurochemical Research
IS - 11
ER -