Neuropathy target esterase (NTE): overview and future Rudy J. Richardson a,b,⇑ , Nichole D. Hein b , Sanjeeva J. Wijeyesakere c , John K. Fink b , Galina F. Makhaeva d a Toxicology Program, University of Michigan, Ann Arbor, MI 48109, USA b Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA c Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109, USA d Institute of Physiologically Active Compounds RAS, Chernogolovka 142432, Russia article info Article history: Available online xxxx Keywords: Neuropathy target esterase (NTE) Organophosphorus (OP) compounds OP compound-induced delayed neuropathy (OPIDN) Patatin-like phospholipase domain containing protein PNPLA Diabetic neuropathy abstract Neuropathy target esterase (NTE) was discovered by M.K. Johnson in his quest for the entity responsible for the striking and mysterious paralysis brought about by certain organophosphorus (OP) esters. His pio- neering work on OP neuropathy led to the view that the biochemical lesion consisted of NTE that had undergone OP inhibition and aging. Indeed, nonaging NTE inhibitors failed to produce disease but pro- tected against neuropathy from subsequently administered aging inhibitors. Thus, inhibition of NTE activity was not the culprit; rather, formation of an abnormal protein was the agent of the disorder. More recently, however, Paul Glynn and colleagues showed that whereas conventional knockout of the NTE gene was embryonic lethal, conditional knockout of central nervous system NTE produced neurodegen- eration, suggesting to these authors that the absence of NTE rather than its presence in some altered form caused disease. We now know that NTE is the 6th member of a 9-protein family called patatin-like phos- pholipase domain-containing proteins, PNPLA1–9. Mutations in the catalytic domain of NTE (PNPLA6) are associated with a slowly developing disease akin to OP neuropathy and hereditary spastic paraplegia called NTE-related motor neuron disorder (NTE-MND). Furthermore, the NTE protein from affected indi- viduals has altered enzymological characteristics. Moreover, closely related PNPLA7 is regulated by insu- lin and glucose. These seemingly disparate findings are not necessarily mutually exclusive, but we need to reconcile recent genetic findings with the historical body of toxicological data indicating that inhibi- tion and aging of NTE are both necessary in order to produce neuropathy from exposure to certain OP compounds. Solving this mystery will be satisfying in itself, but it is also an enterprise likely to pay dividends by enhancing our understanding of the physiological and pathogenic roles of the PNPLA family of proteins in neurological health and disease, including a potential role for NTE in diabetic neuropathy. Ó 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction This paper presents a brief overview of neuropathy target ester- ase (NTE), its relationship to organophosphorus compound-in- duced delayed neuropathy (OPIDN) and motor neuron disease, and a glimpse into directions for future research. 2. OPIDN NTE was discovered in the late 1960s by M.K. Johnson [1,2] as a result of his quest to identify the target protein for initiation of OPIDN, a central–peripheral distal axonopathy of long sensorimo- tor axons in peripheral nerves and spinal cord [3]. Axonal degener- ation and onset of signs and symptoms of distal sensory disturbances and paresis occur 8–10 days after a single suffi- ciently high dose of a neuropathic organophosphorus (OP) compound, and paralysis is usually complete by 11–21 days post-dosing. Adult hens at least 8 months of age are used to study 0009-2797/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cbi.2012.10.024 Abbreviations: AChE, acetylcholinesterase; CBDP, 2-(ortho-cresyl)-4H-1,2,3- benzodioxaphosphoran-2-one; DFP, diisopropylphosphorofluoridate; HSP, heredi- tary spastic paraplegia; mipafox, N,N 0 -diisopropylphosphorodiamidic fluoride; NRE, NTE-related esterase (PNPLA7); NTE, neuropathy target esterase (protein); Nte, NTE-encoding gene; NTE-MND, NTE-related motor neuron disorder; OP, organo- phosphorus; OPIDN, organophosphorus compound-induced delayed neuropathy; paraoxon, diethyl 4-nitrophenylphosphate; PMSF, phenylmethylsulfonyl fluoride; PPA, phenyl phenylacetate; PV, phenyl valerate; PNPLA, patatin-like phospholipase domain containing protein; PNPLA6, patatin-like phospholipase domain containing protein 6 (NTE); pnpla6; PNPLA6-encoding gene; PNPLA7; patatin-like phospholi- pase domain containing protein 7 (NRE); pnpla7, PNPLA7-encoding gene; SAR; structure–activity relationships; SCOTP; saligenin cyclic o-tolyl phosphate; TOCP, tri-o-cresyl phosphate. ⇑ Corresponding author. Address: Toxicology Program, Computational Toxicology Laboratory, The University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109-2029, USA. Tel.: +1 734 936 0769; fax: +1 734 763 8095. E-mail address: rjrich@umich.edu (R.J. Richardson). Chemico-Biological Interactions xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint Please cite this article in press as: R.J. Richardson et al., Neuropathy target esterase (NTE): overview and future, Chemico-Biological Interactions (2012), http://dx.doi.org/10.1016/j.cbi.2012.10.024