Role Of Neuropathy Target Esterase Research Articles

The role of cell cycle-dependent neuropathy target esterase in cell proliferation

Neuropathy target esterase (NTE) is a novel phospholipase B and plays a role in phospholipid homeostasis. Although over-expression of NTE inhibits cell division, the role of NTE in cell proliferation is still unknown. In the current study, we firstly used synchronous HeLa cells to study the expression profile of NTE during the cell cycle. NTE protein and activity are regulated during the cell cycle with highest level at G1 and lowest at G2/M phase. However, NTE mRNA levels are constant during the cell cycle. The role of NTE in cell proliferation was investigated by short hairpin RNA (shRNA) to suppress the expression of NTE. Knockdown of NTE significant down-regulated of NTE expression and reduced the glycerophosphocholine level. However, suppression of NTE did not affect phosphatidylcholine content or cell cycle progression. In addition, NTE was demonstrated to be degraded by the ubiquitin-proteasome pathway. These results suggested for the first time that NTE is a cell cycle-dependent protein, but is not essential for cell proliferation, and the ubiquitin-mediated proteolysis may be involved in the regulation of NTE during the cell cycle.

Role of Neuropathy Target Esterase (NTE) in high NaCl‐induced accumulation of glycerophosphocholine (GPC) by mouse Inner Medullary Collecting Duct 3 (mIMCD3) cells

GPC is an osmoprotective compatible and counteracting organic osmolyte that accumulates in renal inner medullary cells in response to high NaCl and urea. We previously found that high NaCl increases GPC in MDCK cells. The GPC is derived from phosphatidylcholine (PC), catalyzed by increased activity of a phospholipase that was not identified at that time. NTE was recently shown to be a phospholipase that catalyzes production of GPC from PC (Zaccheo et al, JBC 279: 24024, 2004). The purpose of the present studies was to test whether NTE is activated by high NaCl in mIMCD3 cells, resulting in increased GPC. We find that high NaCl increases NTE mRNA 3-fold within 8 hours, and NTE protein by 4-fold at 16 hours and 8-fold at 48 hours. GPC (measured with a sensitive chemiluminescent assay) increases 2.5-fold. Di-isopropyl FluoroPhosphate (DFP) inhibits NTE esterase activity. It reduces GPC accumulation by 30% at 300 mosmol/kg and by 40% at 500 mosmol/kg (NaCl added). Further, a specific siRNA, which reduces NTE protein abundance by 50% at both 300 and 500 mosmol/kg, reduces GPC to the same extent as DFP at both osmolalities. We conclude that high NaCl increases NTE expression and phospholipase B activity, contributing to increased production and accumulation of GPC in mIMCD3 cells.

A review of studies of the delayed neurotoxicity induced by organophosphorus esters

Organophosphorus esters have been used in the plastics industry as antioxidants and plasticizers, in agriculture as insecticides, and in the military as nerve agents. Some of these compounds have organophosphorus ester-induced delayed neurotoxicity (OPIDN) different from the acute toxicity caused by the acetylcholine esterase inhibiting activity. this review describes recent progress in studies on OPIDN and, discusses the future direction of studies. OPIDN is characterized by a more than 7 day incubation period, lower limb paralysis accompanied by axonal degeneration, and age- and species-specificity. Younger animals and rodents are not very sensitive to OPIDN. As well as fast recovery of inhibited neurotoxic esterase or neuropathy target esterase (NTE) in the sciatic nerve, detoxicating mechanisms including carboxylesterases are contributing to age- and species-specificity for OPIDN. Although, anterograde axonal transport does not seem to be affected by OPIDN, slow down of retrograde axonal transport was observed. Inhibition of NTE, and aging of inhibited NTE has been thought to be responsible for OPIDN, but there are some arguments against the role of NTE in OPIDN. Phosphorylation of cytoskeletal proteins by kinases such as calcium dependent-calmodulin kinase II and/or high affinity neurotoxic compound binding site(s) are possible candidates for the initiation of OPIDN. Triphenyl phophite (TPP), a compound commonly used in the plastics industry, has delayed neurotoxicity that is somewhat different from OPIDN. The onset of TPP-induced neuropathy is earlier than that of OPIDN, and rodents are sensitive to TPP. In addition to the axonal damage, cell damage is observed in TPP-induced neuropathy. Mitochondrial energy metabolism-related enzymes could be the target of this neuropathy. Future studies should be focused on the relation of OPIDN to the phosphorylation of cytoskeletal proteins and high affinity binding site(s), and on the development of rodent models. These studies would answer the questions related to OPIDN, and further contribute toward elucidating the pathogenesis of degenerative neuronal diseases.