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Distribution of Secretory Phospholipase A2 XIIA in the Brain and its Role in Lipid Metabolism and Cognition

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Abstract

Phospholipases A2 (PLA2) catalyze the hydrolysis of membrane phospholipids to produce free fatty acids and lysophospholipids, which have important functions in cell signaling. The present study elucidated differential expression of PLA2 isoforms in the rat cortex by quantitative reverse transcription PCR and demonstrated that sPLA2-XIIA had greater messenger RNA expression than iPLA2-VI or cPLA2-IVA in different brain regions, or compared to other sPLA2 isoforms in the prefrontal cortex (PFC) and hippocampus. Western blots identified a 24-kDa band in different regions of the adult brain, and high levels of sPLA2-XIIA protein expression were detected in the PFC, striatum, and thalamus. Electron microscopy showed that sPLA2-XIIA is present in axon terminals and dendrites. Injection of antisense oligonucleotide to sPLA2-XIIA in the PFC and lipidomic analysis showed increase in phospholipid but decrease in lysophospholipid species consistent with decreased catalytic activity of the enzyme, changes in arachidonic acid release, and alterations in sphingolipids. sPLA2-XIIA knockdown also resulted in shorter latency timings in the passive avoidance test, and higher number of errors in the attention set-shifting task, indicating deficits in working memory and attention. Together, the results show an important role of sPLA2-XIIA in lipid metabolism, prefrontal cortical function, and cognition

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References

  1. Titsworth WL, Liu NK, Xu XM (2008) Role of secretory phospholipase A2 in CNS inflammation: implications in traumatic spinal cord injury. CNS Neurol Disord Drug Targets 7(3):254–269

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Farooqui AA, Horrocks LA (2004) Brain phospholipases A2: a perspective on the history. Prostaglandins Leukot Essent Fat Acids 71(3):161–169

    Article  CAS  Google Scholar 

  3. Farooqui AA, Horrocks LA (2006) Phospholipase A2-generated lipid mediators in the brain: the good, the bad, and the ugly. Neuroscientist: Rev J Bringing Neurobiol Neurol Psychiatry 12(3):245–260. doi:10.1177/1073858405285923

    Article  CAS  Google Scholar 

  4. Ong WY, Farooqui T, Farooqui AA (2010) Involvement of cytosolic phospholipase A2, calcium independent phospholipase A2 and plasmalogen selective phospholipase A2 in neurodegenerative and neuropsychiatric conditions. Curr Med Chem 17(25):2746–2763

    Article  PubMed  CAS  Google Scholar 

  5. Lambeau G, Gelb MH (2008) Biochemistry and physiology of mammalian secreted phospholipases A2. Annu Rev Biochem 77:495–520. doi:10.1146/annurev.biochem.76.062405.154007

    Article  PubMed  CAS  Google Scholar 

  6. Murakami M, Taketomi Y, Girard C, Yamamoto K, Lambeau G (2010) Emerging roles of secreted phospholipase A2 enzymes: lessons from transgenic and knockout mice. Biochimie 92(6):561–582

    Article  PubMed  CAS  Google Scholar 

  7. Fourcade O, Simon MF, Viodé C, Rugani N, Leballe F, Ragab A, Fournié B, Sarda L, Chap H (1995) Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell 80(6):919–927

    Article  PubMed  CAS  Google Scholar 

  8. Hanasaki K, Yamada K, Yamamoto S, Ishimoto Y, Saiga A, Ono T, Ikeda M, Notoya M, Kamitani S, Arita H (2002) Potent modification of low density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formation. J Biol Chem 277(32):29116–29124

    Article  PubMed  CAS  Google Scholar 

  9. Pungercar J, Krizaj I (2007) Understanding the molecular mechanism underlying the presynaptic toxicity of secreted phospholipases A2. Toxicon 50(7):871–892

    Article  PubMed  CAS  Google Scholar 

  10. Lambeau G, Lazdunski M (1999) Receptors for a growing family of secreted phospholipases A2. Trends Pharmacol Sci 20(4):162–170

    Article  PubMed  CAS  Google Scholar 

  11. Thwin MM, Ong WY, Fong CW, Sato K, Kodama K, Farooqui AA, Gopalakrishnakone P (2003) Secretory phospholipase A2 activity in the normal and kainate injected rat brain, and inhibition by a peptide derived from python serum. Exp Brain Res Exp Hirnforsch Exp Cereb 150(4):427–433. doi:10.1007/s00221-003-1476-7

    CAS  Google Scholar 

  12. Cunningham TJ, Yao L, Oetinger M, Cort L, Blankenhorn EP, Greenstein JI (2006) Secreted phospholipase A2 activity in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neuroinflammation 3:26. doi:10.1186/1742-2094-3-26

    Article  PubMed  PubMed Central  Google Scholar 

  13. Moses GS, Jensen MD, Lue LF, Walker DG, Sun AY, Simonyi A, Sun GY (2006) Secretory PLA2-IIA: a new inflammatory factor for Alzheimer’s disease. J Neuroinflammation 3:28. doi:10.1186/1742-2094-3-28

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ferrini M, Nardicchi V, Mannucci R, Arcuri C, Nicoletti I, Donato R, Goracci G (2010) Effect of NGF on the subcellular localization of group IIA secretory phospholipase A2 (GIIA) in PC12 cells: role in neuritogenesis. Neurochem Res 35(12):2168–2174. doi:10.1007/s11064-010-0345-6

    Article  PubMed  CAS  Google Scholar 

  15. Masuda S, Yamamoto K, Hirabayashi T, Ishikawa Y, Ishii T, Kudo I, Murakami M (2008) Human group III secreted phospholipase A2 promotes neuronal outgrowth and survival. Biochem J 409(2):429–438. doi:10.1042/BJ20070844

    Article  PubMed  CAS  Google Scholar 

  16. Masuda S, Murakami M, Takanezawa Y, Aoki J, Arai H, Ishikawa Y, Ishii T, Arioka M, Kudo I (2005) Neuronal expression and neuritogenic action of group X secreted phospholipase A2. J Biol Chem 280(24):23203–23214. doi:10.1074/jbc.M500985200

    Article  PubMed  CAS  Google Scholar 

  17. Wei S, Ong WY, Thwin MM, Fong CW, Farooqui AA, Gopalakrishnakone P, Hong W (2003) Group IIA secretory phospholipase A2 stimulates exocytosis and neurotransmitter release in pheochromocytoma-12 cells and cultured rat hippocampal neurons. Neuroscience 121(4):891–898

    Article  PubMed  CAS  Google Scholar 

  18. Than A, Tan Y, Ong WY, Farooqui AA, Chen P (2012) Kainate receptors mediate regulated exocytosis of secretory phospholipase A2 in SH-SY5Y neuroblastoma cells. Neuro-Signals 20(2):72–85. doi:10.1159/000330414

    Article  PubMed  CAS  Google Scholar 

  19. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408

    Article  PubMed  CAS  Google Scholar 

  20. Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37(8):911–917

    Article  PubMed  CAS  Google Scholar 

  21. Shui G, Stebbins JW, Lam BD, Cheong WF, Lam SM, Gregoire F, Kusonoki J, Wenk MR (2011) Comparative plasma lipidome between human and cynomolgus monkey: are plasma polar lipids good biomarkers for diabetic monkeys? PLoS ONE 6(5):e19731. doi:10.1371/journal.pone.0019731

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Shui G, Cheong WF, Jappar IA, Hoi A, Xue Y, Fernandis AZ, Tan BK, Wenk MR (2011) Derivatization-independent cholesterol analysis in crude lipid extracts by liquid chromatography/mass spectrometry: applications to a rabbit model for atherosclerosis. J Chromatogr A 1218(28):4357–4365. doi:10.1016/j.chroma.2011.05.011

    Article  PubMed  CAS  Google Scholar 

  23. Birrell JM, Brown VJ (2000) Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20(11):4320–4324

    PubMed  CAS  Google Scholar 

  24. Young JW, Powell SB, Geyer MA, Jeste DV, Risbrough VB (2010) The mouse attentional-set-shifting task: a method for assaying successful cognitive aging? Cogn Affect Behav Neurosci 10(2):243–251

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gronich J, Konieczkowski M, Gelb MH, Nemenoff RA, Sedor JR (1994) Interleukin 1 alpha causes rapid activation of cytosolic phospholipase A2 by phosphorylation in rat mesangial cells. J Clin Invest 93(3):1224–1233. doi:10.1172/JCI117076

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Leslie CC (1997) Properties and regulation of cytosolic phospholipase A2. J Biol Chem 272(27):16709–16712

    Article  PubMed  CAS  Google Scholar 

  27. Gelb MH, Valentin E, Ghomashchi F, Lazdunski M, Lambeau G (2000) Cloning and recombinant expression of a structurally novel human secreted phospholipase A2. J Biol Chem 275(51):39823–39826

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Molloy GY, Rattray M, Williams RJ (1998) Genes encoding multiple forms of phospholipase A2 are expressed in rat brain. Neurosci Lett 258(3):139–142

    Article  PubMed  CAS  Google Scholar 

  29. Ho IC, Arm JP, Bingham CO III, Choi A, Austen KF, Glimcher LH (2001) A novel group of phospholipase A2s preferentially expressed in type 2 helper T cells. J Biol Chem 276(21):18321–18326

    Article  PubMed  CAS  Google Scholar 

  30. Muñoz-Sanjuán I, Brivanlou AH (2005) Induction of ectopic olfactory structures and bone morphogenetic protein inhibition by Rossy, a group XII secreted phospholipase A2. Mol Cell Biol 25(9):3608–3619

    Article  PubMed  PubMed Central  Google Scholar 

  31. Titsworth WL, Cheng X, Ke Y, Deng L, Burckardt KA, Pendleton C, Liu NK, Shao H, Cao QL, Xu XM (2009) Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. Glia 57(14):1521–1537. doi:10.1002/glia.20867

    Article  PubMed  Google Scholar 

  32. Nakashima S, Ikeno Y, Yokoyama T, Kuwana M, Bolchi A, Ottonello S, Kitamoto K, Arioka M (2003) Secretory phospholipases A2 induce neurite outgrowth in PC12 cells. Biochem J 376(Pt 3):655–666. doi:10.1042/BJ20030830

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Williams EJ, Walsh FS, Doherty P (1994) The production of arachidonic acid can account for calcium channel activation in the second messenger pathway underlying neurite outgrowth stimulated by NCAM, N-cadherin, and L1. J Neurochem 62(3):1231–1234

    Article  PubMed  CAS  Google Scholar 

  34. Smalheiser NR, Dissanayake S, Kapil A (1996) Rapid regulation of neurite outgrowth and retraction by phospholipase A2-derived arachidonic acid and its metabolites. Brain Res 721(1–2):39–48

    Article  PubMed  CAS  Google Scholar 

  35. Ikeno Y, Konno N, Cheon SH, Bolchi A, Ottonello S, Kitamoto K, Arioka M (2005) Secretory phospholipases A2 induce neurite outgrowth in PC12 cells through lysophosphatidylcholine generation and activation of G2A receptor. J Biol Chem 280(30):28044–28052. doi:10.1074/jbc.M503343200

    Article  PubMed  CAS  Google Scholar 

  36. Murzyn K, Rog T, Pasenkiewicz-Gierula M (2005) Phosphatidylethanolamine-phosphatidylglycerol bilayer as a model of the inner bacterial membrane. Biophys J 88(2):1091–1103. doi:10.1529/biophysj.104.048835

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Koduri RS, Grönroos JO, Laine VJ, Le Calvez C, Lambeau G, Nevalainen TJ, Gelb MH (2002) Bactericidal properties of human and murine groups I, II, V, X, and XII secreted phospholipases A2. J Biol Chem 277(8):5849–5857

    Article  PubMed  CAS  Google Scholar 

  38. Huhtinen HT, Grönroos JO, Grönroos JM, Uksila J, Gelb MH, Nevalainen TJ, Laine VJ (2006) Antibacterial effects of human group IIA and group XIIA phospholipase A2 against Helicobacter pylori in vitro. APMIS 114(2):127–130

    Article  PubMed  CAS  Google Scholar 

  39. Rouault M, Le Calvez C, Boilard E, Surrel F, Singer A, Ghomashchi F, Bezzine S, Scarzello S, Bollinger J, Gelb MH, Lambeau G (2007) Recombinant production and properties of binding of the full set of mouse secreted phospholipases A2 to the mouse M-type receptor. Biochemistry 46(6):1647–1662. doi:10.1021/bi062119b

    Article  PubMed  CAS  Google Scholar 

  40. Reynolds CP, Maurer BJ, Kolesnick RN (2004) Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett 206(2):169–180. doi:10.1016/j.canlet.2003.08.034

    Article  PubMed  CAS  Google Scholar 

  41. Mocchetti I (2005) Exogenous gangliosides, neuronal plasticity and repair, and the neurotrophins. Cell Mol Life Sci: CMLS 62(19–20):2283–2294. doi:10.1007/s00018-005-5188-y

    Article  PubMed  CAS  Google Scholar 

  42. Goldman-Rakic PS (1990) Cellular and circuit basis of working memory in prefrontal cortex of nonhuman primates. Prog Brain Res 85:325–335, discussion 335-326

    Article  PubMed  CAS  Google Scholar 

  43. Puumala T, Sirviö J (1998) Changes in activities of dopamine and serotonin systems in the frontal cortex underlie poor choice accuracy and impulsivity of rats in an attention task. Neuroscience 83(2):489–499

    Article  PubMed  CAS  Google Scholar 

  44. de la Presa OS, Innis SM (1999) Docosahexaenoic and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and alpha-linolenic acid deficient diet in formula-fed piglets. J Nutr 129(11):2088–2093

    Google Scholar 

  45. Zimmer L, Durand G, Guilloteau D, Chalon S (1999) n-3 polyunsaturated fatty acid deficiency and dopamine metabolism in the rat frontal cortex. Lipids 34:S251

    Article  PubMed  CAS  Google Scholar 

  46. Biederman J (2005) Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 57(11):1215–1220

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Singapore, through its Competitive Research Project Award.

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Authors and Affiliations

  1. Department of Anatomy, National University of Singapore, Singapore, 119260, Singapore

    Sze-Min Ee, Yew-Long Lo & Wei-Yi Ong

  2. Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, 169608, Singapore

    Yew-Long Lo

  3. Key State Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

    Guanghou Shui

  4. Department of Biochemistry, National University of Singapore, Singapore, 119260, Singapore

    Markus R. Wenk

  5. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, South Korea

    Eun-Joo Shin & Hyoung-Chun Kim

  6. Neurobiology and Ageing Research Programme, National University of Singapore, Singapore, 119260, Singapore

    Wei-Yi Ong

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  1. Sze-Min Ee
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Ee, SM., Lo, YL., Shui, G. et al. Distribution of Secretory Phospholipase A2 XIIA in the Brain and its Role in Lipid Metabolism and Cognition. Mol Neurobiol 50, 60–75 (2014). https://doi.org/10.1007/s12035-014-8635-7

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