TY - JOUR
T1 - Probing mechanisms of axonopathy. Part I
T2 - Protein targets of 1,2-diacetylbenzene, the neurotoxic metabolite of aromatic solvent 1,2-diethylbenzene
AU - Tshala-Katumbay, Desire
AU - Monterroso, Victor
AU - Kayton, Robert
AU - Lasarev, Michael
AU - Sabri, Mohammad
AU - Spencer, Peter
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - Axonal swellings
KW - Gelsolin
KW - Protein disulfide isomerase
KW - Proteomics
KW - Solvent neuropathy
KW - γ-diketones
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U2 - 10.1093/toxsci/kfn103
DO - 10.1093/toxsci/kfn103
M3 - Article
C2 - 18502740
AN - SCOPUS:49249118040
SN - 1096-6080
VL - 105
SP - 134
EP - 141
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -