Involvement of cytoskeletal proteins in the mechanisms of organophosphorus ester-induced delayed neurotoxicity.
1. Organophosphorus ester-induced delayed neurotoxicity (OPIDN) is a neurodegenerative disorder characterized by the presence of swellings in the distal parts of large axons in the central and peripheral nervous systems with subsequent axonal degeneration and paralysis. 2. An early change in OPIDN is enhanced activity and autophosphorylation of Ca2+/calmodulin-dependent kinase II. 3. In OPIDN, there is also a dose- and time-dependent increase in Ca2+/calmodulin-dependent kinase mediated phosphorylation of the cytoskeletal proteins, alpha- and beta-tubulin, microtubule associated protein-2, neurofilament triplet proteins and myelin basic protein. 4. Anomalous hyperphosphorylation of neurofilaments decreases their transport rate down the axon relative to their rate of entry resulting in their accumulation. 5. Consistent with the neurochemical results is the presence of anomalous aggregations of phosphorylated neurofilaments in early stages of OPIDN. 6. These findings suggest that aberrant hyperphosphorylation of cytoskeletal proteins is a post-translational modification involved in the pathogenesis of OPIDN.
Abou-Donia
M B
MB
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA.
D000818:Animals; D001369:Axons / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology; D002645:Chickens; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005500:Follow-Up Studies; D009498:Neurotoxins / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D017933:Peripheral Nervous System / Q000187:drug effects* / Q000473:pathology; D010766:Phosphorylation
D003598:Cytoskeletal Proteins; D009498:Neurotoxins; D009943:Organophosphorus Compounds; D017871:Calcium-Calmodulin-Dependent Protein Kinases