Extracellular ATP and the P2X7receptor in astrocyte-mediated motor neuron death: implications for amyotrophic lateral sclerosis
Tóm tắt
During pathology of the nervous system, increased extracellular ATP acts both as a cytotoxic factor and pro-inflammatory mediator through P2X7 receptors. In animal models of amyotrophic lateral sclerosis (ALS), astrocytes expressing superoxide dismutase 1 (SOD1G93A) mutations display a neuroinflammatory phenotype and contribute to disease progression and motor neuron death. Here we studied the role of extracellular ATP acting through P2X7 receptors as an initiator of a neurotoxic phenotype that leads to astrocyte-mediated motor neuron death in non-transgenic and SOD1G93A astrocytes. We evaluated motor neuron survival after co-culture with SOD1G93A or non-transgenic astrocytes pretreated with agents known to modulate ATP release or P2X7 receptor. We also characterized astrocyte proliferation and extracellular ATP degradation. Repeated stimulation by ATP or the P2X7-selective agonist BzATP caused astrocytes to become neurotoxic, inducing death of motor neurons. Involvement of P2X7 receptor was further confirmed by Brilliant blue G inhibition of ATP and BzATP effects. In SOD1G93A astrocyte cultures, pharmacological inhibition of P2X7 receptor or increased extracellular ATP degradation with the enzyme apyrase was sufficient to completely abolish their toxicity towards motor neurons. SOD1G93A astrocytes also displayed increased ATP-dependent proliferation and a basal increase in extracellular ATP degradation. Here we found that P2X7 receptor activation in spinal cord astrocytes initiated a neurotoxic phenotype that leads to motor neuron death. Remarkably, the neurotoxic phenotype of SOD1G93A astrocytes depended upon basal activation the P2X7 receptor. Thus, pharmacological inhibition of P2X7 receptor might reduce neuroinflammation in ALS through astrocytes.
Tài liệu tham khảo
Rowland LP, Shneider NA: Amyotrophic lateral sclerosis. N Engl J Med. 2001, 344: 1688-1700. 10.1056/NEJM200105313442207.
Rosen DR: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993, 364: 362.
Beckman JS, Estevez AG, Crow JP, Barbeito L: Superoxide dismutase and the death of motoneurons in ALS. Trends Neurosci. 2001, 24: S15-20. 10.1016/S0166-2236(00)01981-0.
Harraz MM, Marden JJ, Zhou W, Zhang Y, Williams A, Sharov VS, Nelson K, Luo M, Paulson H, Schoneich C, Engelhardt JF: SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest. 2008, 118: 659-670.
Papadimitriou D, Le Verche V, Jacquier A, Ikiz B, Przedborski S, Re DB: Inflammation in ALS and SMA: Sorting out the good from the evil. Neurobiol Dis. 2009
Kikuchi H, Almer G, Yamashita S, Guegan C, Nagai M, Xu Z, Sosunov AA, McKhann GM, Przedborski S: Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci USA. 2006, 103: 6025-6030. 10.1073/pnas.0509227103.
Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL, Coyle JT: Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol. 1990, 28: 18-25. 10.1002/ana.410280106.
Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL: An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron. 1995, 14: 1105-1116. 10.1016/0896-6273(95)90259-7.
Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, Reaume AG, Scott RW, Cleveland DW: Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science. 1998, 281: 1851-1854. 10.1126/science.281.5384.1851.
Ilieva H, Polymenidou M, Cleveland DW: Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol. 2009, 187: 761-72. 10.1083/jcb.200908164.
McGeer PL, McGeer EG: Inflammation and the degenerative diseases of aging. Ann N Y Acad Sci. 2004, 1035: 104-116. 10.1196/annals.1332.007.
Barbeito LH, Pehar M, Cassina P, Vargas MR, Peluffo H, Viera L, Estevez AG, Beckman JS: A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Brain Res Rev. 2004, 47: 263-274. 10.1016/j.brainresrev.2004.05.003.
Bruijn LI, Miller TM, Cleveland DW: Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci. 2004, 27: 723-749. 10.1146/annurev.neuro.27.070203.144244.
Vargas MR, Pehar M, Cassina P, Beckman JS, Barbeito L: Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J Neurochem. 2006, 97: 687-696. 10.1111/j.1471-4159.2006.03742.x.
Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC: Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell. 2008, 3: 637-648. 10.1016/j.stem.2008.09.017.
Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K: Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci. 2007, 10: 608-614. 10.1038/nn1885.
Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH: Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell. 2008, 3: 649-657. 10.1016/j.stem.2008.10.001.
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S: Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci. 2007, 10: 615-622. 10.1038/nn1876.
Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A, Robinson KM, Mason RP, Beckman JS, Barbeito L, Radi R: Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci. 2008, 28: 4115-4122. 10.1523/JNEUROSCI.5308-07.2008.
Cassina P, Pehar M, Vargas MR, Castellanos R, Barbeito AG, Estevez AG, Thompson JA, Beckman JS, Barbeito L: Astrocyte activation by fibroblast growth factor-1 and motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem. 2005, 93: 38-46. 10.1111/j.1471-4159.2004.02984.x.
Vargas MR, Pehar M, Cassina P, Martinez-Palma L, Thompson JA, Beckman JS, Barbeito L: Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: consequences for motor neuron survival. J Biol Chem. 2005, 280: 25571-25579. 10.1074/jbc.M501920200.
Hensley K, Abdel-Moaty H, Hunter J, Mhatre M, Mou S, Nguyen K, Potapova T, Pye QN, Qi M, Rice H, Stewart C, Stroukoff K, West M: Primary glia expressing the G93A-SOD1 mutation present a neuroinflammatory phenotype and provide a cellular system for studies of glial inflammation. J Neuroinflammation. 2006, 3: 2-10.1186/1742-2094-3-2.
Pehar M, Vargas MR, Robinson KM, Cassina P, England P, Beckman JS, Alzari PM, Barbeito L: Peroxynitrite transforms nerve growth factor into an apoptotic factor for motor neurons. Free Radic Biol Med. 2006, 41: 1632-1644. 10.1016/j.freeradbiomed.2006.08.010.
Burnstock G: Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discov. 2008, 7: 575-590. 10.1038/nrd2605.
Wang X, Arcuino G, Takano T, Lin J, Peng WG, Wan P, Li P, Xu Q, Liu QS, Goldman SA, Nedergaard M: P2X7 receptor inhibition improves recovery after spinal cord injury. Nat Med. 2004, 10: 821-827. 10.1038/nm1082.
Phillis JW, O'Regan MH, Perkins LM: Adenosine 5'-triphosphate release from the normoxic and hypoxic in vivo rat cerebral cortex. Neurosci Lett. 1993, 151: 94-96. 10.1016/0304-3940(93)90054-O.
Melani A, Turchi D, Vannucchi MG, Cipriani S, Gianfriddo M, Pedata F: ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia. Neurochem Int. 2005, 47: 442-448. 10.1016/j.neuint.2005.05.014.
Piccini A, Carta S, Tassi S, Lasiglie D, Fossati G, Rubartelli A: ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way. Proc Natl Acad Sci USA. 2008, 105: 8067-8072. 10.1073/pnas.0709684105.
North RA: Molecular physiology of P2X receptors. Physiol Rev. 2002, 82: 1013-1067.
Franke H, Gunther A, Grosche J, Schmidt R, Rossner S, Reinhardt R, Faber-Zuschratter H, Schneider D, Illes P: P2X7 receptor expression after ischemia in the cerebral cortex of rats. J Neuropathol Exp Neurol. 2004, 63: 686-699.
Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH, Han X, Takano T, Wang S, Sim FJ, Goldman SA, Nedergaard M: The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J Neurosci. 2007, 27: 12255-12266. 10.1523/JNEUROSCI.3404-07.2007.
Narcisse L, Scemes E, Zhao Y, Lee SC, Brosnan CF: The cytokine IL-1beta transiently enhances P2X7 receptor expression and function in human astrocytes. Glia. 2005, 49: 245-258. 10.1002/glia.20110.
John GR, Simpson JE, Woodroofe MN, Lee SC, Brosnan CF: Extracellular nucleotides differentially regulate interleukin-1beta signaling in primary human astrocytes: implications for inflammatory gene expression. J Neurosci. 2001, 21: 4134-4142.
Panenka W, Jijon H, Herx LM, Armstrong JN, Feighan D, Wei T, Yong VW, Ransohoff RM, MacVicar BA: P2X7-like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase. J Neurosci. 2001, 21: 7135-7142.
Ryu JK, McLarnon JG: Block of purinergic P2X(7) receptor is neuroprotective in an animal model of Alzheimer's disease. Neuroreport. 2008, 19: 1715-1719. 10.1097/WNR.0b013e3283179333.
Matute C, Torre I, Perez-Cerda F, Perez-Samartin A, Alberdi E, Etxebarria E, Arranz AM, Ravid R, Rodriguez-Antiguedad A, Sanchez-Gomez M, Domercq M: P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J Neurosci. 2007, 27: 9525-9533. 10.1523/JNEUROSCI.0579-07.2007.
Diaz-Hernandez M, Diez-Zaera M, Sanchez-Nogueiro J, Gomez-Villafuertes R, Canals JM, Alberch J, Miras-Portugal MT, Lucas JJ: Altered P2X7-receptor level and function in mouse models of Huntington's disease and therapeutic efficacy of antagonist administration. FASEB J. 2009, 23: 1893-1906. 10.1096/fj.08-122275.
Peng W, Cotrina ML, Han X, Yu H, Bekar L, Blum L, Takano T, Tian GF, Goldman SA, Nedergaard M: Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. Proc Natl Acad Sci USA. 2009, 106: 12489-12493. 10.1073/pnas.0902531106.
Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P: COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006, 6: 12-10.1186/1471-2377-6-12.
Casanovas A, Hernandez S, Tarabal O, Rossello J, Esquerda JE: Strong P2X4 purinergic receptor-like immunoreactivity is selectively associated with degenerating neurons in transgenic rodent models of amyotrophic lateral sclerosis. J Comp Neurol. 2008, 506: 75-92. 10.1002/cne.21527.
D'Ambrosi N, Finocchi P, Apolloni S, Cozzolino M, Ferri A, Padovano V, Pietrini G, Carri MT, Volonte C: The proinflammatory action of microglial P2 receptors is enhanced in SOD1 models for amyotrophic lateral sclerosis. J Immunol. 2009, 183: 4648-4656. 10.4049/jimmunol.0901212.
Cassina P, Peluffo H, Pehar M, Martinez-Palma L, Ressia A, Beckman JS, Estevez AG, Barbeito L: Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis. J Neurosci Res. 2002, 67: 21-29. 10.1002/jnr.10107.
Henderson CE, Bloch-Gallego E, Camu W: Purification and culture of embryonic motor neurons. 1995, Oxford: IRL Press
Estevez AG, Sahawneh MA, Lange PS, Bae N, Egea M, Ratan RR: Arginase 1 regulation of nitric oxide production is key to survival of trophic factor-deprived motor neurons. J Neurosci. 2006, 26: 8512-8516. 10.1523/JNEUROSCI.0728-06.2006.
Wink MR, Braganhol E, Tamajusuku AS, Casali EA, Karl J, Barreto-Chaves ML, Sarkis JJ, Battastini AM: Extracellular adenine nucleotides metabolism in astrocyte cultures from different brain regions. Neurochem Int. 2003, 43: 621-628. 10.1016/S0197-0186(03)00094-9.
Teng RJ, Ye YZ, Parks DA, Beckman JS: Urate produced during hypoxia protects heart proteins from peroxynitrite-mediated protein nitration. Free Radic Biol Med. 2002, 33: 1243-1249. 10.1016/S0891-5849(02)01020-1.
Santos CX, Anjos EI, Augusto O: Uric acid oxidation by peroxynitrite: multiple reactions, free radical formation, and amplification of lipid oxidation. Arch Biochem Biophys. 1999, 372: 285-294. 10.1006/abbi.1999.1491.
Neary JT, Kang Y: Signaling from P2 nucleotide receptors to protein kinase cascades induced by CNS injury: implications for reactive gliosis and neurodegeneration. Mol Neurobiol. 2005, 31: 95-103. 10.1385/MN:31:1-3:095.
Rathbone MP, Middlemiss PJ, Kim JK, Gysbers JW, DeForge SP, Smith RW, Hughes DW: Adenosine and its nucleotides stimulate proliferation of chick astrocytes and human astrocytoma cells. Neurosci Res. 1992, 13: 1-17. 10.1016/0168-0102(92)90030-G.
Ciccarelli R, Di Iorio P, D'Alimonte I, Giuliani P, Florio T, Caciagli F, Middlemiss PJ, Rathbone MP: Cultured astrocyte proliferation induced by extracellular guanosine involves endogenous adenosine and is raised by the co-presence of microglia. Glia. 2000, 29: 202-211. 10.1002/(SICI)1098-1136(20000201)29:3<202::AID-GLIA2>3.0.CO;2-C.
Cotrina ML, Nedergaard M: Physiological and pathological functions of P2X7 receptor in the spinal cord. Purinergic Signal. 2009, 5: 223-232. 10.1007/s11302-009-9138-2.
Surprenant A: Functional properties of native and cloned P2X receptors. Ciba Found Symp. 1996, 198: 208-219. discussion 219-222
Bianchi BR, Lynch KJ, Touma E, Niforatos W, Burgard EC, Alexander KM, Park HS, Yu H, Metzger R, Kowaluk E, Jarvis MF, van Biesen T: Pharmacological characterization of recombinant human and rat P2X receptor subtypes. Eur J Pharmacol. 1999, 376: 127-138. 10.1016/S0014-2999(99)00350-7.
Skaper SD, Facci L, Culbert AA, Evans NA, Chessell I, Davis JB, Richardson JC: P2X(7) receptors on microglial cells mediate injury to cortical neurons in vitro. Glia. 2006, 54: 234-242. 10.1002/glia.20379.
Braun N, Zhu Y, Krieglstein J, Culmsee C, Zimmermann H: Upregulation of the enzyme chain hydrolyzing extracellular ATP after transient forebrain ischemia in the rat. J Neurosci. 1998, 18: 4891-4900.
Nedeljkovic N, Bjelobaba I, Lavrnja I, Stojkov D, Pekovic S, Rakic L, Stojiljkovic M: Early temporal changes in ecto-nucleotidase activity after cortical stab injury in rat. Neurochem Res. 2008, 33: 873-879. 10.1007/s11064-007-9529-0.
Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW: Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008, 11: 251-253. 10.1038/nn2047.