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Neurotoxicants and the cytoskeleton.
1Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232-2562, USA. doyle.graham@mcmail.vanderbilt.edu
Current Opinion in Neurology
|February 17, 2000
Summary
Occupational toxicants like n-hexane cause distal axonopathies by cross-linking neurofilaments, leading to axonal swelling. Other toxicants impair synaptic vesicle transport by affecting microtubule-associated proteins.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Occupational and environmental toxicants can cause distal axonopathies, damaging nerve cell axons.
- The axonal cytoskeleton, particularly neurofilaments and microtubules, is a target for toxicant-induced damage.
Purpose of the Study:
- To elucidate the molecular mechanisms by which different toxicants induce distal axonopathies.
- To differentiate the pathways leading to neurofilament cross-linking versus impaired axonal transport.
Main Methods:
- Analysis of toxicant metabolism and interaction with cytoskeletal components.
- Investigation of protein adducts and cross-linking in affected axons.
- Assessment of axonal transport and synaptic vesicle dynamics.
Main Results:
- 2,5-hexanedione, a metabolite of n-hexane and methyl n-butyl ketone, covalently cross-links neurofilaments, causing axonal swellings.
- Carbon disulfide induces a similar axonopathy via neurofilament cross-linking through distinct reactions.
- Acrylamide and ethylene oxide adduct proteins but do not cross-link neurofilaments; they impair axonal transport by affecting microtubule-associated proteins like kinesin.
Conclusions:
- Toxicant-induced distal axonopathies result from distinct molecular mechanisms targeting the axonal cytoskeleton.
- Neurofilament cross-linking and impaired axonal transport represent two primary pathways of toxicant neurotoxicity.