Probing mechanisms of axonopathy. Part I: Protein targets of 1,2-diacetylbenzene, the neurotoxic metabolite of aromatic solvent 1,2-diethylbenzene

Desire Tshala-Katumbay, Victor Monterroso, Robert Kayton, Michael Lasarev, Mohammad Sabri, Peter Spencer

Research output: Contribution to journalArticle

16 Scopus citations

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 γ-diketone-like 1,2-diacetylbenzene (1,2-DAB), but not its 1,3-DAB isomer, reacts with ε-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.

Original languageEnglish (US)
Pages (from-to)134-141
Number of pages8
JournalToxicological Sciences
Volume105
Issue number1
DOIs
StatePublished - 2008

Keywords

  • Axonal swellings
  • Gelsolin
  • Protein disulfide isomerase
  • Proteomics
  • Solvent neuropathy
  • γ-diketones

ASJC Scopus subject areas

  • Toxicology

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