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The Journal of Neuroscience, September 16, 2009, 29(37):11594-11600; doi:10.1523/JNEUROSCI.3007-09.2009

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Brief Communications
Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance

David J. Read,¹ Yong Li,¹ Moses V. Chao,² John B. Cavanagh,³ and Paul Glynn¹

¹Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom, ²Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, and ³Department of Clinical Neuroscience, Institute of Psychiatry, London SE5 8AF, United Kingdom

Correspondence should be addressed to Paul Glynn, Medical Research Council Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK. Email: pg8{at}le.ac.uk

The enzyme neuropathy target esterase (NTE) is present in neurons and deacylates the major membrane phospholipid, phosphatidylcholine (PtdCho). Mutation of the NTE gene or poisoning by neuropathic organophosphates—chemical inhibitors of NTE—causes distal degeneration of long spinal axons in humans. However, analogous neuropathological changes have not been reported in nestin-cre:NTEfl/fl mice with NTE-deficient neural tissue. Furthermore, altered PtdCho homeostasis has not been detected in NTE-deficient vertebrates. Here, we describe distal degeneration of the longest spinal axons in 3-week-old nestin-cre:NTEfl/fl mice and in adult C57BL/6J mice after acute dosing with a neuropathic organophosphate: in both groups early degenerative lesions were followed by swellings comprising accumulated axoplasmic material. In mice dosed acutely with organophosphate, maximal numbers of lesions, in the longest spinal sensory axon tract, were attained within days and were preceded by a transient rise in neural PtdCho. In nestin-cre:NTEfl/fl mice, sustained elevation of PtdCho over many months was accompanied by progressive degeneration and massive swelling of axons in sensory and motor spinal tracts and by increasing hindlimb dysfunction. Axonal lesion distribution closely resembled that in hereditary spastic paraplegia (HSP). The importance of defective membrane trafficking in HSP and the association of NTE with the endoplasmic reticulum—the starting point for the constitutive secretory pathway and transport of neuronal materials into axons—prompted investigation for a role of NTE in secretion. Cultured NTE-deficient neurons displayed modestly impaired secretion, consistent with neuronal viability and damage in vivo initially restricted to distal parts of the longest axons.

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Received June 25, 2009; accepted Aug. 3, 2009.

Correspondence should be addressed to Paul Glynn, Medical Research Council Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK. Email: pg8{at}le.ac.uk

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