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New Insights into Mechanisms of γ-Diketone-Induced Axonopathy

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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 γ-diketone axonopathy. These findings open opportunities for new therapeutic testing (e.g., supplementation with denitrosylating THX) in γ-diketone-induced axonal disease.

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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.

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Authors and Affiliations

  1. Department of Neurology, School of Medicine, Portland, OR, USA

    Desire Tshala-Katumbay, Mohammad Sabri & Peter Spencer

  2. Center for Research on Occupational & Environmental Toxicology, Oregon Health & Science University, 3181 S.W. Jackson Park Road, Mail Code L606, Portland, OR, 97239, USA

    Desire Tshala-Katumbay, Mohammad Sabri & Peter Spencer

  3. Neuroscience Research Unit, St-Luc Hospital, Montreal, Canada

    Paul Desjardins & Roger Butterworth

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  1. Desire Tshala-Katumbay
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  2. Paul Desjardins
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Correspondence to Desire Tshala-Katumbay.

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Tshala-Katumbay, D., Desjardins, P., Sabri, M. et al. New Insights into Mechanisms of γ-Diketone-Induced Axonopathy. Neurochem Res 34, 1919–1923 (2009). https://doi.org/10.1007/s11064-009-9977-9

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  • DOI: https://doi.org/10.1007/s11064-009-9977-9

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