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Evidence that mouse brain neuropathy target esterase is a lysophospholipase
Gary B Quistad1, Carrolee Barlow, Christopher J Winrow
1Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, University of California, Berkeley, CA 94720-3112, USA.
Abstract:
Neuropathy target esterase (NTE) is inhibited by several organophosphorus (OP) pesticides, chemical warfare agents, lubricants, and plasticizers, leading to OP-induced delayed neuropathy in people (>30,000 cases of human paralysis) and hens (the best animal model for this demyelinating disease). The active site region of NTE as a recombinant protein preferentially hydrolyzes lysolecithin, suggesting that this enzyme may be a type of lysophospholipase (LysoPLA) with lysolecithin as its physiological substrate. This hypothesis is tested here in mouse brain by replacing the phenyl valerate substrate of the standard NTE assay with lysolecithin for an "NTE-LysoPLA" assay with four important findings. First, NTE-LysoPLA activity, as the NTE activity, is 41-45% lower in Nte-haploinsufficient transgenic mice than in their wild-type littermates. Second, the potency of six delayed neurotoxicants or toxicants as in vitro inhibitors varies from IC50 0.02 to 13,000 nM and is essentially the same for NTE-LysoPLA and NTE (r2 = 0.98). Third, the same six delayed toxicants administered i.p. to mice at multiple doses inhibit brain NTE-LysoPLA and NTE to the same extent (r2 = 0.90). Finally, their in vivo inhibition of brain NTE-LysoPLA generally correlates with delayed toxicity. Therefore, OP-induced delayed toxicity in mice, and possibly the hyperactivity associated with NTE deficiency, may be due to NTE-LysoPLA inhibition, leading to localized accumulation of lysolecithin, a known demyelinating agent and receptor-mediated signal transducer. This mouse model has some features in common with OP-induced delayed neuropathy in hens and people but differs in the neuropathological signs and apparently the requirement for NTE aging.
Insights
Neuropathy target esterase (NTE) acts as a lysophospholipase (LysoPLA), hydrolyzing lysolecithin. Organophosphorus toxicants inhibiting NTE-LysoPLA cause delayed neuropathy by accumulating lysolecithin.
Area of Science:
- Biochemistry
- Neuroscience
- Toxicology
Background:
- Neuropathy target esterase (NTE) is implicated in organophosphorus (OP)-induced delayed neuropathy.
- Recombinant NTE preferentially hydrolyzes lysolecithin, suggesting a lysophospholipase (LysoPLA) function.
- OP-induced delayed neuropathy affects humans and hens, causing paralysis and demyelination.
Purpose of the Study:
- To test the hypothesis that NTE functions as a LysoPLA with lysolecithin as its physiological substrate.
- To investigate the role of NTE-LysoPLA activity in OP-induced delayed neurotoxicity using a mouse model.
Main Methods:
- Developed an 'NTE-LysoPLA' assay using lysolecithin instead of phenyl valerate.
- Compared NTE-LysoPLA and NTE activities in Nte-haploinsufficient transgenic mice and wild-type littermates.
- Assessed in vitro and in vivo inhibition of NTE-LysoPLA and NTE by six delayed neurotoxicants in mice.
Main Results:
- NTE-LysoPLA activity was significantly lower (41-45%) in Nte-haploinsufficient mice.
- In vitro and in vivo inhibition potencies of toxicants were similar for NTE-LysoPLA and NTE (r² = 0.98 and r² = 0.90, respectively).
- In vivo inhibition of NTE-LysoPLA correlated with delayed neurotoxicity.
Conclusions:
- NTE likely functions as a LysoPLA, with lysolecithin as a physiological substrate.
- Inhibition of NTE-LysoPLA by OP toxicants may cause delayed neuropathy via lysolecithin accumulation.
- This mouse model offers insights into OP-induced delayed toxicity, though differences in pathology exist compared to hens and humans.