Disease relevance of Pnpla6

• These studies show that genetic or chemical reduction of Nte activity results in a neurological phenotype of hyperactivity in mammals and indicate that EOPF toxicity occurs directly through inhibition of Nte without the requirement for Nte gain of function or aging [1].
• Nte(+/-) and wild-type mice treated with 1 mg per kg of body weight of EOPF have elevated motor activity, showing that even minor reduction of Nte activity leads to hyperactivity [1].
• Thus, these results identify a physiological role for NTE in the nervous system and indicate that a loss-of-function mechanism may contribute to neurodegenerative diseases characterized by vacuolation and neuronal loss [2].
• 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) [3].
• Inhibition of neurite outgrowth in differentiating mouse N2a neuroblastoma cells by phenyl saligenin phosphate: effects on MAP kinase (ERK 1/2) activation, neurofilament heavy chain phosphorylation and neuropathy target esterase activity [4].

High impact information on Pnpla6

• Neuropathy target esterase (NTE) was recently shown to be a phospholipase B that catalyzes production of GPC from phosphatidylcholine [5].
• Further, the lower renal inner medullary interstitial NaCl concentration that occurs chronically in ClCK1(-/-) mice and acutely in normal mice given furosemide is associated with lower NTE mRNA and protein [5].
• Neuropathy target esterase catalyzes osmoprotective renal synthesis of glycerophosphocholine in response to high NaCl [5].
• Diisopropyl fluorophosphate, which inhibits NTE esterase activity, reduces GPC accumulation, as does an siRNA that specifically reduces NTE protein abundance [5].
• Absence of NTE resulted in disruption of the endoplasmic reticulum, vacuolation of nerve cell bodies, and abnormal reticular aggregates [2].

Biological context of Pnpla6

• 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 [3].
• Drosophila mutants for the homolog gene of NTE, swisscheese (sws), indicated a possible involvement of sws in the regulation of axon-glial cell interaction during glial wrapping [2].
• 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) [3].
• Age-dependent neurodegeneration resulting from widespread apoptosis of neurons and glia characterize the Drosophila Swiss Cheese (SWS) mutant [6].
• To investigate the physiological functions of NTE, we inactivated its gene by targeted mutagenesis in embryonic stem cells [6].

Anatomical context of Pnpla6

• Here we show that loss of NTE leads to prominent neuronal pathology in the hippocampus and thalamus and also defects in the cerebellum [2].
• Histological analysis indicated that NTE is essential for the formation of the labyrinth layer and survival and differentiation of secondary giant cells [6].
• Additionally, impairment of vasculogenesis in the yolk sacs and embryos of null mutant conceptuses suggested that NTE is also required for normal blood vessel development [6].
• Actions of two highly potent organophosphorus neuropathy target esterase inhibitors in mammalian cell lines [7].
• Neuropathy target esterase (NTE) reacts with those organophosphates, which cause paralysis with swelling and degeneration of distal parts of long nerves in the legs and spinal cord [8].

Associations of Pnpla6 with chemical compounds

• 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 [3].
• This species difference is reevaluated with two optimized inhibitors of hen brain NTE by examining them for potential neurotoxic effects in mice [9].
• Diazinon had no effect on the activity of neuropathy target esterase [10].
• Neither ecothiopate nor paraoxon inhibited NTE, so this prejunctional effect is not likely to be related to 'classical' OP-induced delayed neuropathy [11].
• Homogenates from hens were more sensitive to NTE inhibition induced by phenyl saligenin phosphate (PSP), an active congener of TOTP, than were homogenates from less susceptible species (mouse, rat, bovine) [12].

Other interactions of Pnpla6

• Finally, their in vivo inhibition of brain NTE-LysoPLA generally correlates with delayed toxicity [3].
• By comparison, a non-neurotoxic organophosphate, ecothiopate (0.5 mumol/kg), was a potent inhibitor of diaphragm acetylcholinesterase and produced a large increase in postjunctional jitter but ecothiopate did not inhibit brain neuropathy target esterase and had no effect on prejunctional jitter [13].

Analytical, diagnostic and therapeutic context of Pnpla6

• 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 [3].
• Subacute neurotoxic signs are always associated with at least 80% inhibition of brain NTE activity 16-24 hr after treatment [9].

References