Axonal Degeneration and Neuropathy Target Esterase

Paul Glynn 1
  • 1 MRC Toxicology Unit, University of Leicester, United Kingdom

Axonal Degeneration and Neuropathy Target Esterase

This brief review summarises recent observations which suggest a possible mechanism for organophosphate-induced delayed neuropathy (OPIDN). Neuropathy target esterase (NTE) has been shown to deacylate endoplasmic reticulum (ER) membrane phosphatidylcholine (PtdCho). Raised levels of PtdCho are present in the brains of swiss cheese/NTE mutant Drosophila together with abnormal membrane structures, axonal and dendritic degeneration and neural cell loss. Similar vacuolated pathology is found in the brains of mice with brain-specific deletion of the NTE gene and, in old age, these mice show clinical and histopathological features of neuropathy resembling those in wild-type mice chronically dosed with tri-ortho-cresylphosphate. It is suggested that OPIDN results from the loss of NTE's phospholipase activity which in turn causes ER malfunction and perturbation of axonal transport and glial-axonal interactions.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Cavanagh JB. The significance of the "dying back" process in experimental and human neurological disease. Int Rev Exp Pathol 1964;3:219-67.

  • Ehrich M, Jortner BS. Organophosphorus-induced delayed neuropathy. In: Krieger R, editor. Handbook of Pesticide Toxicology. Vol. 2. 2nd ed. San Diego (CA): Academic Press; 2001 . p. 987-1012.

  • Johnson MK. The target for initiation of delayed neurotoxicity by organophosphorus esters: biochemical studies and toxicological applications. Rev Biochem Toxciol 1982;4:141-212.

  • Lotti M. Organophosphorus compounds. In: Spencer PS, Schaumburg HH, Ludolph AC, editors. Experimental and Clinical Neurotoxicology. 2nd ed. New York (USA): Oxford University Press; 2000. p. 897-925.

  • Lush MJ, Li Y, Read DJ, Willis AC, Glynn P. Neuropathy target esterase and a homologous Drosophila neurodegeneration associated mutant protein contain a novel domain conserved from bacteria to man. Biochem J 1998;332:1-4.

  • Li Y, Dinsdale D, Glynn P. Protein domains, catalytic activity and subcellular distribution of neuropathy target esterase in mammalian cells. J Biol Chem 2003;278:8820-5.

  • Zaccheo O, Dinsdale D, Meacock PA, Glynn P. Neuropathy target esterase and its yeast homologue degrade phosphatidylcholine to glycerophosphocholine in living cells. J Biol Chem 2004;279:24024-33.

  • Mühlig-Versen M, Bettencourt da Cruz A, Tschäpe J-A, Moser M, Büttner R, Athenstaedt K, Glynn P, Kretzschmar D. Loss of Swiss cheese/Neuropathy target esterase activity causes disruption of phosphatidylcholine homeostasis and neuronal and glial death in adult Drosophila. J Neurosci 2005;25:2865-73.

  • Akassoglou K, Malester B, Xu J, Tessarollo L, Rosenbluth J, Chao M. Brain-specific deletion of neuropathy target esterase/swiss cheese results in neurodegeneration. Proc Natl Acad Sci (USA) 2004;101:5075-80.

  • Veronesi B, Padilla S, Blackmon K, Pope C. Murine susceptibility to organophosphorus-induced delayed neuropathy. Toxciol Appl Pharmacol 1991;107:311-24.

  • Lapadula DM, Patton SE, Campbell GA, Abou-Donia MB. Characterisation of delayed neurotoxicity in the mouse following chronic oral administration of tri-o-cresyl phosphate Toxicol Appl Pharmacol 1985;79:83-90.

  • Johnson MK, Lauwerys R. Protection by some carbamates against the delayed neurotoxic effects of di-isopropyl phosphorofluoridate. Nature 1969;222:1066-7.

  • Johnson MK. The primary biochemical lesion leading to the delayed neurotoxic effects of some organophosphorus esters. J Neurochem 1974;23:785-9.

  • Johnson MK. Organophosphates and delayed neuropathy-is NTE alive and well? Toxicol Appl Pharmacol 1990;102:385-99.

  • Glynn P. Neural development and neurodegeneration: two faces of neuropathy target esterase. Prog Neurobiol 2000;61:61-74.

  • Lotti M. The pathogenesis of organophosphate polyneuropathy. Crit Rev Toxicol 1992;21:465-87.

  • Moretto A, Lotti M, Sabri MI, Spencer PS. Progressive deficit of retrograde axonal transport is associated with the pathogenesis of di-n-butyl dichlorvos axonopathy. J Neurochem 1987;49:1515-22.

  • Kretzschmar D, Hasan G, Sharma S, Heisenberg M, Benzer S. The swisscheese mutant causes glial hyperwrapping and brain degeneration in Drosophila. J Neuroscience 1997;17:7425-32.


Journal + Issues