Neuropathy target esterase explained

Neuropathy target esterase, also known as patatin-like phospholipase domain-containing protein 6 (PNPLA6), is an esterase enzyme that in humans is encoded by the PNPLA6 gene.^{[1] [2] [3] [4]}

Neuropathy target esterase is a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the endoplasmic reticulum in both neurons and non-neuronal cells.^[4]

Function

Neuropathy target esterase is an enzyme with phospholipase B activity: it sequentially hydrolyses both fatty acids from the major membrane lipid phosphatidylcholine, generating water-soluble glycerophosphocholine.^{[5] [6]} In eukaryotic cells, NTE is anchored to the cytoplasmic face of the endoplasmic reticulum membrane. In mammals, it is particularly abundant in neurons, the placenta, and the kidney.^{[7] [8] [9] [10] [11]} Loss of NTE activity results in abnormally-elevated levels of phosphatidylcholine in the brain and impairment of the constitutive secretory pathway in neurons.^{[1] [12] [13]}

In the kidney, the expression of neuropathy target esterase is regulated by TonEBP as part of osmolyte production when the kidney produces concentrated urine.^[14]

Clinical significance

Mutations in this gene result in autosomal-recessive spastic paraplegia. The protein is also the target for neurodegeneration induced by organophosphorus compounds and chemical warfare agents.^[4]

Recessively-inherited mutations in NTE that substantially reduce its catalytic activity cause a rare form of hereditary spastic paraplegia (SPG39), in which distal parts of long spinal axons degenerate leading to limb weakness and paralysis.^{[15] [16]} Organophosphate-induced delayed neuropathy a paralysing syndrome with distal degeneration of long axons results from poisoning with neuropathic organophosphorus compounds that irreversibly inhibit NTE.^{[17] [18] [19] [20] [21] [22]}

Further reading

• Glynn P . Neural development and neurodegeneration: two faces of neuropathy target esterase. . Prog. Neurobiol. . 61 . 1 . 61–74 . 2000 . 10759065 . 10.1016/S0301-0082(99)00043-X . 20322620 .
• Maroni M, Bleecker ML . Neuropathy target esterase in human lymphocytes and platelets. . Journal of Applied Toxicology . 6 . 1 . 1–7 . 1986 . 3958422 . 10.1002/jat.2550060102 . 21763818 .
• Bertoncin D, Russolo A, Caroldi S, Lotti M . Neuropathy target esterase in human lymphocytes. . Arch. Environ. Health . 40 . 3 . 139–44 . 1985 . 4026382 . 10.1080/00039896.1985.10545905.
• Gurba PE, Richardson RJ . Partial characterization of neurotoxic esterase of human placenta. . Toxicol. Lett. . 15 . 1 . 13–7 . 1983 . 6836585 . 10.1016/0378-4274(83)90162-5 . 2027.42/25337 . free .
• van Tienhoven M, Atkins J, Li Y, Glynn P . Human neuropathy target esterase catalyzes hydrolysis of membrane lipids. . J. Biol. Chem. . 277 . 23 . 20942–8 . 2002 . 11927584 . 10.1074/jbc.M200330200 . free .
• Strausberg RL . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . Feingold EA . Grouse LH . Derge . JG . Klausner . RD . Collins . FS . Wagner . L . Shenmen . CM . Schuler . GD . 2002PNAS...9916899M . free .
• Li Y, Dinsdale D, Glynn P . Protein domains, catalytic activity, and subcellular distribution of neuropathy target esterase in Mammalian cells . J. Biol. Chem. . 278 . 10 . 8820–5 . 2003 . 12514188 . 10.1074/jbc.M210743200 . free .
• Winrow CJ . Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity . Nat. Genet. . 33 . 4 . 477–85 . 2003 . 12640454 . 10.1038/ng1131 . Hemming ML . Allen DM . Quistad . Gary B. . Casida . John E. . Barlow . Carrolee . free .
• Zaccheo O, Dinsdale D, Meacock PA, Glynn P . Neuropathy target esterase and its yeast homologue degrade phosphatidylcholine to glycerophosphocholine in living cells . J. Biol. Chem. . 279 . 23 . 24024–33 . 2004 . 15044461 . 10.1074/jbc.M400830200 . free .
• Beausoleil SA . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proc. Natl. Acad. Sci. U.S.A. . 101 . 33 . 12130–5 . 2004 . 15302935 . 10.1073/pnas.0404720101 . 514446 . Jedrychowski M . Schwartz D . Elias . JE . Villén . J . Li . J . Cohn . MA . Cantley . LC . Gygi . SP . 2004PNAS..10112130B . free .
• Chang PA . Inhibition of neuropathy target esterase expressing by antisense RNA does not affect neural differentiation in human neuroblastoma (SK-N-SH) cell line . Mol. Cell. Biochem. . 272 . 1–2 . 47–54 . 2005 . 16010971 . 10.1007/s11010-005-6753-2 . Wu YJ . Chen R . Li . Ming . Li . Wei . Qin . Qi-Lian . 20498617 .
• Chang PA, Chen R, Wu YJ . Reduction of neuropathy target esterase does not affect neuronal differentiation, but moderate expression induces neuronal differentiation in human neuroblastoma (SK-N-SH) cell line . Brain Res. Mol. Brain Res. . 141 . 1 . 30–8 . 2006 . 16122834 . 10.1016/j.molbrainres.2005.07.012 . 22182434 .
• Kimura K . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 10.1101/gr.4039406 . 1356129 . Wakamatsu A . Suzuki Y . Ota . T . Nishikawa . T . Yamashita . R . Yamamoto . J . Sekine . M . Tsuritani . K .
• Chang PA . Liu ChY . Chen R . Wu YJ . Effect of over-expression of neuropathy target esterase on mammalian cell proliferation . Cell Prolif. . 39 . 5 . 429–40 . 2006 . 16987144 . 10.1111/j.1365-2184.2006.00399.x . 6496609 .
• Chen R . Down-regulation of neuropathy target esterase by protein kinase C activation with PMA stimulation . Mol. Cell. Biochem. . 302 . 1–2 . 179–85 . 2007 . 17385009 . 10.1007/s11010-007-9439-0 . Chang PA . Long DX . Yang . Lin . Wu . Yi-Jun . 1235494 .

Notes and References

1. Lush MJ, Li Y, Read DJ, Willis AC, Glynn P . Neuropathy target esterase and a homologous Drosophila neurodegeneration-associated mutant protein contain a novel domain conserved from bacteria to man . 332 . Biochem J . (Pt 1) . 1–4 . Aug 1998 . Pt 1 . 9576844 . 1219444 . 10.1042/bj3320001.
2. Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ . Characterization of the human patatin-like phospholipase family . J Lipid Res . 47 . 9 . 1940–9 . Aug 2006 . 16799181 . 10.1194/jlr.M600185-JLR200 . free .
3. Kienesberger PC, Oberer M, Lass A, Zechner R . Mammalian patatin domain containing proteins: a family with diverse lipolytic activities involved in multiple biological functions . J Lipid Res . 50 Suppl . Supplement. S63–8 . Apr 2009 . 19029121 . 2674697 . 10.1194/jlr.R800082-JLR200 . free .
4. Web site: Entrez Gene: PNPLA6 patatin-like phospholipase domain containing 6.
5. Glynn P . Neuropathy target esterase and phospholipid deacylation . Biochim. Biophys. Acta . 1736 . 2 . 87–93 . September 2005 . 16137924 . 10.1016/j.bbalip.2005.08.002 .
6. Fernández-Murray JP, McMaster CR . Phosphatidylcholine synthesis and its catabolism by yeast neuropathy target esterase 1 . Biochim. Biophys. Acta . 1771 . 3 . 331–6 . March 2007 . 16731034 . 10.1016/j.bbalip.2006.04.004 .
7. Li Y, Dinsdale D, Glynn P . Protein domains, catalytic activity, and subcellular distribution of neuropathy target esterase in Mammalian cells . J. Biol. Chem. . 278 . 10 . 8820–5 . March 2003 . 12514188 . 10.1074/jbc.M210743200 . free .
8. Zaccheo O, Dinsdale D, Meacock PA, Glynn P . Neuropathy target esterase and its yeast homologue degrade phosphatidylcholine to glycerophosphocholine in living cells . J. Biol. Chem. . 279 . 23 . 24024–33 . June 2004 . 15044461 . 10.1074/jbc.M400830200 . free .
9. Glynn P, Holton JL, Nolan CC, Read DJ, Brown L, Hubbard A, Cavanagh JB . Neuropathy target esterase: immunolocalization to neuronal cell bodies and axons . Neuroscience . 83 . 1 . 295–302 . March 1998 . 9466418 . 10.1016/S0306-4522(97)00388-6. 7075276 .
10. Moser M, Li Y, Vaupel K, Kretzschmar D, Kluge R, Glynn P, Buettner R . Placental failure and impaired vasculogenesis result in embryonic lethality for neuropathy target esterase-deficient mice . Mol. Cell. Biol. . 24 . 4 . 1667–79 . February 2004 . 14749382 . 344166 . 10.1128/mcb.24.4.1667-1679.2004.
11. Gallazzini M, Ferraris JD, Kunin M, Morris RG, Burg MB . Neuropathy target esterase catalyzes osmoprotective renal synthesis of glycerophosphocholine in response to high NaCl . Proc. Natl. Acad. Sci. U.S.A. . 103 . 41 . 15260–5 . October 2006 . 17015841 . 1622810 . 10.1073/pnas.0607133103 . 2006PNAS..10315260G . free .
12. Mühlig-Versen M, da Cruz AB, Tschäpe JA, Moser M, Büttner R, Athenstaedt K, Glynn P, Kretzschmar D . Loss of Swiss cheese/neuropathy target esterase activity causes disruption of phosphatidylcholine homeostasis and neuronal and glial death in adult Drosophila . J. Neurosci. . 25 . 11 . 2865–73 . March 2005 . 15772346 . 1182176 . 10.1523/JNEUROSCI.5097-04.2005 .
13. Read DJ, Li Y, Chao MV, Cavanagh JB, Glynn P . Neuropathy target esterase is required for adult vertebrate axon maintenance . J. Neurosci. . 29 . 37 . 11594–600 . September 2009 . 19759306 . 10.1523/JNEUROSCI.3007-09.2009 . 3849655 .
14. Gallazzini . M.. Burg . M. B.. 10.1152/physiol.00009.2009. What's New About Osmotic Regulation of Glycerophosphocholine. Physiology. 24. 4. 245–249. 2009. 19675355. 2943332.
15. Rainier S, Bui M, Mark E, Thomas D, Tokarz D, Ming L, Delaney C, Richardson RJ, Albers JW, Matsunami N, Stevens J, Coon H, Leppert M, Fink JK . Neuropathy target esterase gene mutations cause motor neuron disease . Am. J. Hum. Genet. . 82 . 3 . 780–5 . March 2008 . 18313024 . 2427280 . 10.1016/j.ajhg.2007.12.018 .
16. Rainier S, Albers JW, Dyck PJ, Eldevik OP, Wilcock S, Richardson RJ, Fink JK . Motor neuron disease due to neuropathy target esterase gene mutation: clinical features of the index families . Muscle Nerve . 43 . 1 . 19–25 . January 2011 . 21171093 . 10.1002/mus.21777 . 2027.42/78477 . 1621142 . free .
17. Lotti M, Moretto A . Organophosphate-induced delayed polyneuropathy . Toxicol Rev . 24 . 1 . 37–49 . 2005 . 16042503 . 10.2165/00139709-200524010-00003. 29313644 .
18. CAVANAGH JB . The toxic effects of triortho-cresyl phosphate on the nervous system; an experimental study in hens . J. Neurol. Neurosurg. Psychiatry . 17 . 3 . 163–72 . August 1954 . 13192490 . 503178 . 10.1136/jnnp.17.3.163.
19. CASIDA JE, ETO M, BARON RL . Biological activity of a trio-cresyl phosphate metabolite . Nature . 191 . 4796. 1396–7 . September 1961 . 13877086 . 10.1038/1911396a0 . 1961Natur.191.1396C . 4195141 .
20. Johnson MK . The delayed neurotoxic effect of some organophosphorus compounds. Identification of the phosphorylation site as an esterase . Biochem. J. . 114 . 4 . 711–7 . October 1969 . 4310054 . 1184957 . 10.1042/bj1140711.
21. Glynn P, Read DJ, Guo R, Wylie S, Johnson MK . Synthesis and characterization of a biotinylated organophosphorus ester for detection and affinity purification of a brain serine esterase: neuropathy target esterase . Biochem. J. . 301 (Pt 2) . 2. 551–6 . July 1994 . 8043002 . 1137116 . 10.1042/bj3010551.
22. Read DJ, Li Y, Chao MV, Cavanagh JB, Glynn P . Organophosphates induce distal axonal damage, but not brain oedema, by inactivating neuropathy target esterase . Toxicol. Appl. Pharmacol. . 245 . 1 . 108–15 . May 2010 . 20188121 . 10.1016/j.taap.2010.02.010 .