The cytoskeleton as a target for organophosphorus ester-induced delayed neurotoxicity (OPIDN).
Although the immediate action of organophosphorus esters is the inhibition of acetylcholinesterase, some of these compounds also produce a neurodegenerative disorder known as organophosphorus ester-induced delayed neurotoxicity (OPIDN). Tri-o-cresyl phosphate (TOCP) first produced this condition in humans and later in sensitive animal species. OPIDN is characterized by a delay period prior to onset of ataxia and paralysis. The neuropathologic lesions are Wallerian-type degeneration of the axon and myelin in the distal parts of the large tracts in both the central and peripheral nervous systems. In the past decade we have demonstrated that the pathognomonic features of OPIDN are an aberrant increase in autophosphorylation of calcium/calmodulin kinase II (CaM kinase II) and an increase in phosphorylation of cytoskeletal proteins, i.e., MAPs, tubulin, neurofilament triplet proteins, and myelin basic protein. Protein kinase-mediated phosphorylation of cytoskeletal proteins plays a critical role in regulating the growth and maintenance of the axon. We hypothesize that, in OPIDN, hyperphosphorylation of cytoskeletal proteins and axonal swelling are causally linked. Hyperphosphorylation of cytoskeletal proteins decreases their transport rate down the axon relative to their rate of entry into the axon, thus leading to their accumulation. Consistent with this hypothesis is our finding of the anomalous accumulation of phosphorylated neurofilament aggregates in the central and peripheral axons of hens treated with TOCP.
Abou-Donia
M B
MB
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004952:Esters / Q000633:toxicity; D006801:Humans; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010766:Phosphorylation
D003598:Cytoskeletal Proteins; D004952:Esters; D009943:Organophosphorus Compounds