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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Translocator protein (TSPO): the new story of the old protein in neuroinflammation

  • Lee, Younghwan (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Park, Youngjin (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Nam, Hyeri (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Lee, Ji-Won (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Yu, Seong-Woon (Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
  • Received : 2019.10.22
  • Published : 2020.01.31
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Abstract

Translocator protein (TSPO), also known as peripheral benzodiazepine receptor, is a transmembrane protein located on the outer mitochondria membrane (OMM) and mainly expressed in glial cells in the brain. Because of the close correlation of its expression level with neuropathology and therapeutic efficacies of several TSPO binding ligands under many neurological conditions, TSPO has been regarded as both biomarker and therapeutic target, and the biological functions of TSPO have been a major research focus. However, recent genetic studies with animal and cellular models revealed unexpected results contrary to the anticipated biological importance of TSPO and cast doubt on the action modes of the TSPO-binding drugs. In this review, we summarize recent controversial findings on the discrepancy between pharmacological and genetic studies of TSPO and suggest some future direction to understand this old and mysterious protein.

Keywords

References

  1. Wallace DC (2012) Mitochondria and cancer. Nat Rev Cancer 12, 685 https://doi.org/10.1038/nrc3365
  2. Green DR, Galluzzi L and Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109-1112 https://doi.org/10.1126/science.1201940
  3. Chen H and Chan DC (2009) Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases. Hum Mol Genet 18, R169-R176 https://doi.org/10.1093/hmg/ddp326
  4. Pfanner N, Warscheid B and Wiedemann N (2019) Mitochondrial proteins: from biogenesis to functional networks. Nat Rev Mol Cell Biol 20, 267-284 https://doi.org/10.1038/s41580-018-0092-0
  5. Braestrup C, Albrechtsen R and Squires RF (1977) High densities of benzodiazepine receptors in human cortical areas. Nature 269, 702-704 https://doi.org/10.1038/269702a0
  6. Papadopoulos V (1998) Structure and function of the peripheral-type benzodiazepine receptor in steroidogenic cells. Proc Soc Exp Biol Med 217, 130-142 https://doi.org/10.3181/00379727-217-44215
  7. Azarashvili T, Krestinina O, Yurkov I, Evtodienko Y and Reiser G (2005) High-affinity peripheral benzodiazepine receptor ligand, PK11195, regulates protein phosphorylation in rat brain mitochondria under control of Ca2+. J Neurochem 94, 1054-1062 https://doi.org/10.1111/j.1471-4159.2005.03260.x
  8. Hirsch JD, Beyer CF, Malkowitz L, Beer B and Blume AJ (1989) Mitochondrial benzodiazepine receptors mediate inhibition of mitochondrial respiratory control. Mol Pharm 35, 157-163
  9. Hirsch T, Decaudin D, Susin SA et al (1998) PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection. Exp Cell Res 241, 426-434 https://doi.org/10.1006/excr.1998.4084
  10. Lee D, Kang S, Lee R et al (2004) Effects of peripheral benzodiazepine receptor ligands on proliferation and differentiation of human mesenchymal stem cells. J Cell Physiol 198, 91-99 https://doi.org/10.1002/jcp.10391
  11. Kim T and Pae AN (2016) Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: A patent review (2010-2015; part 1). Expert Opin Ther Pat 26, 1325-1351 https://doi.org/10.1080/13543776.2016.1230606
  12. Fan J, Lindemann P, GJ Feuilloley M and Papadopoulos V (2012) Structural and functional evolution of the translocator protein (18 kDa). Curr Mol Med 12, 369-386 https://doi.org/10.2174/1566524011207040369
  13. Yeliseev AA, Krueger KE and Kaplan S (1997) A mammalian mitochondrial drug receptor functions as a bacterial "oxygen" sensor. Proc Natl Acad Sci U S A 94, 5101-5106 https://doi.org/10.1073/pnas.94.10.5101
  14. Chapalain A, Chevalier S, Orange N, Murillo L, Papadopoulos V and Feuilloley MG (2009) Bacterial ortholog of mammalian translocator protein (TSPO) with virulence regulating activity. PLoS One 4, e6096 https://doi.org/10.1371/journal.pone.0006096
  15. Riond J, Leplatois P, Laurent P et al (1991) Expression and pharmacological characterization of the human peripheraltype benzodiazepine receptor in yeast. Eur J Pharmacol 208, 307-312 https://doi.org/10.1016/0922-4106(91)90076-T
  16. Fan J, Rone MB and Papadopoulos V (2009) Translocator protein 2 is involved in cholesterol redistribution during erythropoiesis. J Biol Chem 284, 30484-30497 https://doi.org/10.1074/jbc.M109.029876
  17. Li F, Liu J, Zheng Y, Garavito RM and Ferguson-Miller S (2015) Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism. Science 347, 555-558 https://doi.org/10.1126/science.1260590
  18. Jaremko L, Jaremko M, Giller K, Becker S and Zweckstetter M (2014) Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science 343, 1363-1366 https://doi.org/10.1126/science.1248725
  19. Guo Y, Kalathur RC, Liu Q et al (2015) Structure and activity of tryptophan-rich TSPO proteins. Science 347, 551-555 https://doi.org/10.1126/science.aaa1534
  20. Veenman L, Vainshtein A, Yasin N, Azrad M and Gavish M (2016) Tetrapyrroles as endogenous TSPO ligands in eukaryotes and prokaryotes: Comparisons with synthetic ligands. Int J Mol Sci 17, 880 https://doi.org/10.3390/ijms17060880
  21. Owen DR, Yeo AJ, Gunn RN et al (2012) An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 32, 1-5 https://doi.org/10.1038/jcbfm.2011.147
  22. Toor JS and Sikka SC (2017) Developmental and Reproductive Disorders-Role of Endocrine Disruptors in Testicular Toxicity; in Rep Dev Toxicol 1111-1121, Elsevier,
  23. Papadopoulos V, Mukhin A, Costa E and Krueger K (1990) The peripheral-type benzodiazepine receptor is functionally linked to Leydig cell steroidogenesis. J Bioll Chem 265, 3772-3779 https://doi.org/10.1016/S0021-9258(19)39661-9
  24. Chung J-Y, Chen H, Midzak A, Burnett A, Papadopoulos V and Zirkin BR (2013) Drug ligand-induced activation of translocator protein (TSPO) stimulates steroid production by aged brown Norway rat Leydig cells. Endocrinology 154, 2156-2165 https://doi.org/10.1210/en.2012-2226
  25. Papadopoulos V, Amri H, Li H, Boujrad N, Vidic B and Garnier M (1997) Targeted disruption of the peripheral-type benzodiazepine receptor gene inhibits steroidogenesis in the R2C Leydig tumor cell line. J Biol Chem 272, 32129-32135 https://doi.org/10.1074/jbc.272.51.32129
  26. Hauet T, Yao ZX, Bose HS et al (2005) Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into leydig cell mitochondria. Mol Endocrinol 19, 540-554 https://doi.org/10.1210/me.2004-0307
  27. McEnery MW, Snowman AM, Trifiletti RR and Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci U S A 89, 3170-3174 https://doi.org/10.1073/pnas.89.8.3170
  28. Buki A, Okonkwo DO, Wang KK and Povlishock JT (2000) Cytochrome c release and caspase activation in traumatic axonal injury. J Neurosci 20, 2825-2834 https://doi.org/10.1523/jneurosci.20-08-02825.2000
  29. Lemasters JJ, Theruvath TP, Zhong Z and Nieminen A-L (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta Bioenerg 1787, 1395-1401 https://doi.org/10.1016/j.bbabio.2009.06.009
  30. Azarashvili T, Krestinina O, Baburina Y et al (2015) Combined effect of G3139 and TSPO ligands on Ca2+-induced permeability transition in rat brain mitochondria. Arch Biochem Biophys 587, 70-77 https://doi.org/10.1016/j.abb.2015.10.012
  31. Shoshan-Barmatz V, Pittala S and Mizrachi D (2019) VDAC1 and the TSPO: Expression, Interactions, and Associated Functions in Health and Disease States. Int J Mol Sci 20, 3348 https://doi.org/10.3390/ijms20133348
  32. Selvaraj V and Stocco DM (2015) The changing landscape in translocator protein (TSPO) function. Trends Endocrinol Metab 26, 341-348 https://doi.org/10.1016/j.tem.2015.02.007
  33. Kim S, Kim N, Park S et al (2019) Tanycytic TSPO inhibition induces lipophagy to regulate lipid metabolism and improve energy balance. Autophagy [Epub ahead of print]
  34. Lee JW, Nam H and Yu SW (2016) Systematic analysis of translocator protein 18 kDa (TSPO) ligands on toll-like receptors-mediated pro-inflammatory responses in microglia and astrocytes. Exp Neurobiol 25, 262-268 https://doi.org/10.5607/en.2016.25.5.262
  35. Notter T, Coughlin JM, Sawa A and Meyer U (2018) Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry. Mol Psychiatry 23, 36 https://doi.org/10.1038/mp.2017.232
  36. Christensen A and Pike CJ (2018) TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice. Neurosci Lett 683, 7-12 https://doi.org/10.1016/j.neulet.2018.06.029
  37. Gong J, Szego EM, Leonov A et al (2019) Translocator protein ligand protects against neurodegeneration in the MPTP mouse model of Parkinsonism. J Neurosci 39, 3752-3769 https://doi.org/10.1523/JNEUROSCI.2070-18.2019
  38. Daugherty DJ, Selvaraj V, Chechneva OV, Liu XB, Pleasure DE and Deng W (2013) A TSPO ligand is protective in a mouse model of multiple sclerosis. EMBO Mol Med 5, 891-903 https://doi.org/10.1002/emmm.201202124
  39. Verleye M, Akwa Y, Liere P et al (2005) The anxiolytic etifoxine activates the peripheral benzodiazepine receptor and increases the neurosteroid levels in rat brain. Pharmacol Biochem Behar 82, 712-720 https://doi.org/10.1016/j.pbb.2005.11.013
  40. Okuyama S, Chaki S, Yoshikawa R et al (1999) Neuropharmacological profile of peripheral benzodiazepine receptor agonists, DAA1097 and DAA1106. Life Sci 64, 1455-1464 https://doi.org/10.1016/S0024-3205(99)00079-X
  41. Wang D-s, Tian Z, Guo Y-y et al (2015) Anxiolytic-like effects of translocator protein (TSPO) ligand ZBD-2 in an animal model of chronic Pain. Mol Pain 11, 16 https://doi.org/10.1186/s12990-015-0013-6
  42. Da Pozzo E, Giacomelli C, Barresi E et al (2015) Targeting the 18-kDa translocator protein: recent perspectives for neuroprotection. Biochem Soc Trans 43, 559-565 https://doi.org/10.1042/BST20150028
  43. Kim EJ and Yu SW (2015) Translocator protein 18 kDa (TSPO): old dogma, new mice, new structure, and new questions for neuroprotection. Neural Regen Res 10, 878 https://doi.org/10.4103/1673-5374.158338
  44. Kupa LdVK, Drewes CC, Barioni ED, Neves CL, Sampaio SC and Farsky SH (2017) Role of Translocator 18 KDa Ligands in the Activation of Leukotriene B4 Activated G-Protein Coupled Receptor and Toll Like Receptor-4 Pathways in Neutrophils. Front Pharmacol 8, 766 https://doi.org/10.3389/fphar.2017.00766
  45. Lee JW, Kim LE, Shim HJ, Kim EK, Hwang WC and Yu S-W (2016) A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation. Biochem Biophys Res Comm 474, 587-593 https://doi.org/10.1016/j.bbrc.2016.04.080
  46. Wang W, Zhang L, Zhang X et al (2016) Lentiviralmediated overexpression of the 18 kDa translocator protein (TSPO) in the hippocampal dentate gyrus ameliorates LPS-induced cognitive impairment in mice. Front Pharmacol 7, 384
  47. Bae KR, Shim HJ, Balu D, Kim SR and Yu SW (2014) Translocator protein 18 kDa negatively regulates inflammation in microglia. J Neuroimmune Pharmacol 9, 424-437 https://doi.org/10.1007/s11481-014-9540-6
  48. Wang M, Wang X, Zhao L et al (2014) Macrogliamicroglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J Neurosci 34, 3793-3806 https://doi.org/10.1523/JNEUROSCI.3153-13.2014
  49. Deczkowska A and Schwartz M (2018) Targeting neuro-immune communication in neurodegeneration: Challenges and opportunities. J Exp Med 215, 2702-2704 https://doi.org/10.1084/jem.20181737
  50. Schwartz M (2017) Can immunotherapy treat neurodegeneration? Science 357, 254-255 https://doi.org/10.1126/science.aai8231
  51. Notter T, Coughlin JM, Gschwind T et al (2018) Translational evaluation of translocator protein as a marker of neuroinflammation in schizophrenia. Mol Psychiatry 23, 323 https://doi.org/10.1038/mp.2016.248
  52. Owen DR, Narayan N, Wells L et al (2017) Proinflammatory activation of primary microglia and macrophages increases 18 kDa translocator protein expression in rodents but not humans. J Cereb Blood Flow Metab 37, 2679-2690 https://doi.org/10.1177/0271678X17710182
  53. Daugherty DJ, Chechneva O, Mayrhofer F and Deng W (2016) The hGFAP-driven conditional TSPO knockout is protective in a mouse model of multiple sclerosis. Sci Rep 6, 22556 https://doi.org/10.1038/srep22556
  54. Milenkovic VM, Slim D, Bader S et al (2019) CRISPR-Cas9 Mediated TSPO Gene Knockout alters Respiration and Cellular Metabolism in Human Primary Microglia Cells. Int J Mol Sci 20, 3359 https://doi.org/10.3390/ijms20133359
  55. Alam MM, Lee J and Lee S-Y (2017) Recent progress in the development of TSPO PET ligands for neuroinflammation imaging in neurological diseases. Nucl Med Mol Imaging 51, 283-296 https://doi.org/10.1007/s13139-017-0475-8
  56. Debruyne J, Versijpt J, Van Laere K et al (2003) PET visualization of microglia in multiple sclerosis patients using [11C] PK11195. Eur J Neurol 10, 257-264 https://doi.org/10.1046/j.1468-1331.2003.00571.x
  57. Cagnin A, Brooks DJ, Kennedy AM et al (2001) In-vivo measurement of activated microglia in dementia. The Lancet 358, 461-467 https://doi.org/10.1016/S0140-6736(01)05625-2
  58. Gerhard A, Pavese N, Hotton G et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 21, 404-412 https://doi.org/10.1016/j.nbd.2005.08.002
  59. Turner M, Cagnin A, Turkheimer F et al (2004) Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15, 601-609 https://doi.org/10.1016/j.nbd.2003.12.012
  60. Chauveau F, Boutin H, Van Camp N et al (2011) In vivo imaging of neuroinflammation in the rodent brain with [11 C] SSR180575, a novel indoleacetamide radioligand of the translocator protein (18 kDa). Eur J Nucl Med Mol Imaging 38, 509-514 https://doi.org/10.1007/s00259-010-1628-5
  61. Li L, Chen T, Stanton JD, Sueyoshi T, Negishi M and Wang H (2008) The peripheral benzodiazepine receptor ligand 1-(2-chlorophenyl-methylpropyl)-3-isoquinoline-carboxamide is a novel antagonist of human constitutive androstane receptor. Mol Pharmacol 74, 443-453 https://doi.org/10.1124/mol.108.046656
  62. Bordet T, Buisson B, Michaud M et al (2007) Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther 322, 709-720 https://doi.org/10.1124/jpet.107.123000
  63. Schaller S, Paradis S, Ngoh GA et al (2010) TRO40303, a new cardioprotective compound, inhibits mitochondrial permeability transition. J Pharmacol Exp Ther 333, 696-706 https://doi.org/10.1124/jpet.110.167486
  64. Nguyen N, Fakra E, Pradel V et al (2006) Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice. Hum Psychopharmacol 21, 139-149 https://doi.org/10.1002/hup.757
  65. do Rego JL, Vaudry D and Vaudry H (2015) The nonbenzodiazepine anxiolytic drug etifoxine causes a rapid, receptor-independent stimulation of neurosteroid biosynthesis. PLoS One 10, e0120473 https://doi.org/10.1371/journal.pone.0120473
  66. Rupprecht R, Rammes G, Eser D et al (2009) Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science 325, 490-493 https://doi.org/10.1126/science.1175055
  67. Biswas L, Farhan F, Reilly J, Bartholomew C and Shu X (2018) TSPO Ligands Promote Cholesterol Efflux and Suppress Oxidative Stress and Inflammation in Choroidal Endothelial Cells. Int J Mol Sci 19, 3740 https://doi.org/10.3390/ijms19123740
  68. Tu LN, Morohaku K, Manna PR et al (2014) Peripheral benzodiazepine receptor/translocator protein global knockout mice are viable with no effects on steroid hormone biosynthesis. J Biol Chem 289, 27444-27454 https://doi.org/10.1074/jbc.M114.578286
  69. Morohaku K, Pelton SH, Daugherty DJ, Butler WR, Deng W and Selvaraj V (2014) Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. Endocrinology 155, 89-97 https://doi.org/10.1210/en.2013-1556
  70. Sileikyte J, Blachly-Dyson E, Sewell R et al (2014) Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (Translocator Protein of 18 kDa (TSPO)). J Biol Chem 289, 13769-13781 https://doi.org/10.1074/jbc.M114.549634
  71. Zhao AH, Tu LN, Mukai C et al (2016) Mitochondrial translocator protein (TSPO) function is not essential for heme biosynthesis. J Biol Chem 291, 1591-1603 https://doi.org/10.1074/jbc.M115.686360
  72. Tu LN, Zhao AH, Stocco DM and Selvaraj V (2015) PK11195 effect on steroidogenesis is not mediated through the translocator protein (TSPO). Endocrinology 156, 1033-1039 https://doi.org/10.1210/en.2014-1707
  73. Hatty CR, Le Brun AP, Lake V et al (2014) Investigating the interactions of the 18 kDa translocator protein and its ligand PK11195 in planar lipid bilayers. Biochim Biophys Acta Biomembr 1838, 1019-1030 https://doi.org/10.1016/j.bbamem.2013.12.013
  74. Bader S, Wolf L, Milenkovic VM et al (2019) Differential effects of TSPO ligands on mitochondrial function in mouse microglia cells. Psychoneuroendocrinology 106, 65-76 https://doi.org/10.1016/j.psyneuen.2019.03.029