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ToxSci Advance Access originally published online on May 22, 2008
Toxicological Sciences 2008 105(1):134-141; doi:10.1093/toxsci/kfn103
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Probing Mechanisms of Axonopathy. Part I: Protein Targets of 1,2-Diacetylbenzene, the Neurotoxic Metabolite of Aromatic Solvent 1,2-Diethylbenzene

Desire Tshala-Katumbay*,{ddagger},1, Victor Monterroso{dagger}, Robert Kayton{ddagger}, Michael Lasarev{ddagger}, Mohammad Sabri*,{ddagger} and Peter Spencer*,{ddagger}

* Department of Neurology {dagger} Department of Comparative Medicine, School of Medicine {ddagger} Center for Research on Occupational & Environmental Toxicology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239

1 To whom correspondence should be addressed at Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, 3181 S.W. Jackson Park Road, mail code L606, Portland, OR 97239. Fax: (503) 494-6831. E-mail: tshalad{at}ohsu.edu.

Received April 4, 2008; accepted May 16, 2008


  Abstract

Motor neuron axonopathy in diseases such as amyotrophic lateral sclerosis can be modeled and probed with neurotoxic chemicals that induce similar patterns of pathology, such as axonal spheroids that represent focal accumulation of anterogradely transported neurofilaments (NFs). The aromatic {gamma}-diketone–like 1,2-diacetylbenzene (1,2-DAB), but not its 1,3-DAB isomer, reacts with {epsilon}-amino- or sulfyhydryl groups of (neuro)proteins, forms adducts, and causes NFs to accumulate at proximal sites of elongate motor axons. We exploit the protein-reactive properties of neurotoxic 1,2-DAB versus the nonprotein-reactive properties of non-neurotoxic 1,3-DAB to unveil proteomic changes associated with this type of pathology. We used two-dimensional differential in-gel electrophoresis (2D-DIGE), matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry to analyze the lumbosacral spinal cord proteome of adult Sprague-Dawley rats treated systemically with 20 mg/kg/day 1,2-DAB, equimolar dose of 1,3-DAB, or equivalent volume of vehicle (saline containing 2% acetone), 5 days a week, for 2 weeks. 1,2-DAB significantly altered the expression of protein disulfide isomerase, an enzyme involved in protein folding, and gelsolin, an actin-capping and -severing protein. Modifications of these two proteins have been incriminated in the pathogenesis of nerve fiber degeneration. Protein-reactive and neurotoxic 1,2-DAB appears to be excellent tool to dissect mechanisms of nerve fiber (axon) degeneration.

Key Words: axonal swellings; {gamma}-diketones; gelsolin; protein disulfide isomerase; proteomics; solvent neuropathy.


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D. Tshala-Katumbay, V. Monterroso, R. Kayton, M. Lasarev, M. Sabri, and P. Spencer
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[Abstract] [Full Text] [PDF]


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