FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of huntington disease

Human Molecular Genetics

Volumn 23, Issue 9, 2014, Pages 2251-2265

  Di Pardo, Alba ^a   Amico, Enrico ^a   Favellato, Mariagrazia ^a   Castrataro, Roberta ^a   Fucile, Sergio ^a,b   Squitieri, Ferdinando ^a   Maglione, Vittorio ^a  

^a IRCCS NEUROMED   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; FINGOLIMOD; GANGLIOSIDE GM1; HUNTINGTIN; MITOGEN ACTIVATED PROTEIN KINASE; PROTEIN KINASE B; SPHINGOSINE 1 PHOSPHATE RECEPTOR; SPHINGOSINE KINASE 2; PHOSPHOTRANSFERASE; PROPANEDIOL DERIVATIVE; SPHINGOSINE; SPHINGOSINE KINASE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN ATROPHY; CHRONIC DRUG ADMINISTRATION; CONNECTOME; CONTROLLED STUDY; DRUG EFFICACY; ENZYME ACTIVITY; GABAERGIC TRANSMISSION; HUNTINGTON CHOREA; IMMUNOHISTOCHEMISTRY; LIFESPAN; MOTOR PERFORMANCE; MOUSE; MOUSE MODEL; NEUROPATHOLOGY; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SURVIVAL; ANALOGS AND DERIVATIVES; ANIMAL; BRAIN; CELL LINE; DISEASE MODEL; DRUG EFFECTS; HUNTINGTON DISEASE; IMMUNOBLOTTING; MALE; METABOLISM; NEURODEGENERATIVE DISEASES; PATHOLOGY; REAL TIME POLYMERASE CHAIN REACTION; TRANSGENIC MOUSE;

ANIMALS; BRAIN; CELL LINE; DISEASE MODELS, ANIMAL; HUNTINGTON DISEASE; IMMUNOBLOTTING; IMMUNOHISTOCHEMISTRY; MALE; MICE; MICE, TRANSGENIC; NEURODEGENERATIVE DISEASES; PHOSPHOTRANSFERASES (ALCOHOL GROUP ACCEPTOR); PROPYLENE GLYCOLS; REAL-TIME POLYMERASE CHAIN REACTION; SPHINGOSINE;

EID: 84897541254     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddt615     Document Type: Article

References (63)

1. Novak, M.J. and Tabrizi, S.J. (2011) Huntington's disease: clinical presentation and treatment. Int. Rev. Neurobiol., 98, 297-323.
2. T.H.s. D.C.R. Group. (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell, 72, 971-983.
3. Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B.R., Goffredo, D., Conti, L., MacDonald, M.E., Friedlander, R.M., Silani, V., Hayden, M.R. et al. (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science, 293, 493-498.
4. Borrell-pages, M., Zala, D., Humbert, S. and Saudou, F. (2006) Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies. Cell. Mol. Life. Sci., 63, 2642-2660.
5. Maglione, V., Marchi, P., Di Pardo, A., Lingrell, S., Horkey, M., Tidmarsh, E. and Sipione, S. (2010) Impaired ganglioside metabolism in Huntington's disease and neuroprotective role of GM1. J. Neurosci., 30, 4072-4080.
6. Chiba, K. and Adachi, K. (2012) Discovery of fingolimod, the sphingosine 1-phosphate receptor modulator and its application for the therapy of multiple sclerosis. Future Med. Chem., 4, 771-781.
7. Ali, R., Nicholas, R.S. and Muraro, P.A. (2013) Drugs in development for relapsing multiple sclerosis. Drugs, 73, 625-650.
8. Spiegel, S. and Milstien, S. (2003) Exogenous and intracellularly generated sphingosine 1-phosphate can regulate cellular processes by divergent pathways. Biochem. Soc. Trans., 31, 1216-1219.
9. Brinkmann, V. (2007) Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol. Ther., 115, 84-105.
10. Dev, K.K., Mullershausen, F., Mattes, H., Kuhn, R.R., Bilbe, G., Hoyer, D. and Mir, A. (2008) Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol. Ther., 117, 77-93.
11. Meno-Tetang, G.M., Li, H., Mis, S., Pyszczynski, N., Heining, P., Lowe, P. and Jusko, W.J. (2006) Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in rats after oral and intravenous doses. Drug Metab. Dispos., 34, 1480-1487.
12. Billich, A., Bornancin, F., Devay, P., Mechtcheriakova, D., Urtz, N. and Baumruker, T. (2003) Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J. Biol. Chem., 278, 47408-47415.
13. Brinkmann, V., Davis, M.D., Heise, C.E., Albert, R., Cottens, S., Hof, R., Bruns, C., Prieschl, E., Baumruker, T., Hiestand, P. et al. (2002) Theimmune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem., 277, 21453-21457.
14. Miron, V.E., Schubart, A. and Antel, J.P. (2008) Central nervous system-directed effects of FTY720 (fingolimod). J. Neurol. Sci., 274, 13-17.
15. Osinde, M., Mullershausen, F. and Dev, K.K. (2007) Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology, 52, 1210-1218.
16. Coelho, R.P., Payne, S.G., Bittman, R., Spiegel, S. and Sato-Bigbee, C. (2007) The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J. Pharmacol. Exp. Ther., 323, 626-635.
17. Deogracias, R., Matsumoto, T., Klein, C., Klin, C., Yazdani, M., bible, M. and Barde, Y. (2008) FTY720 induces BDNF production in neuronal cell cultures. Neurology, 70, A373.
18. Di Menna, L., Molinaro, G., Di Nuzzo, L., Riozzi, B., Zappulla, C., Pozzilli, C., Turrini, R., Caraci, F., Copani, A., Battaglia, G. et al. (2012) Fingolimod protects cultured cortical neurons against excitotoxic death. Pharmacol. Res., 67, 1-9.
19. Deogracias, R., Yazdani, M., Dekkers, M.P., Guy, J., Ionescu, M.C., Vogt, K.E. and Barde, Y.A. (2012) Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA, 109, 14230-14235.
20. Bajwa, A., Jo, S.K., Ye, H., Huang, L., Dondeti, K.R., Rosin, D.L., Haase, V.H., Macdonald, T.L., Lynch, K.R. and Okusa, M.D. (2010) Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury. J. Am. Soc. Nephrol., 21, 955-965.
21. Stessin, A.M., Gursel, D.B., Schwartz, A., Parashar, B., Kulidzhanov, F.G., Sabbas, A.M., Boockvar, J., Nori, D. and Wernicke, A.G. (2012) FTY720, sphingosine 1-phosphate receptor modulator, selectively radioprotects hippocampal neural stem cells. Neurosci. Lett., 516, 253-258.
22. Brunati, A.M., Tibaldi, E., Carraro, A., Gringeri, E., D'Amico, F. Jr., Toninello, A., Massimino, M.L., Pagano, M.A., Nalesso, G. and Cillo, U. (2008) Cross-talk between PDGF and S1P signalling elucidates the inhibitory effect and potential antifibrotic action of the immunomodulator FTY720 in activated HSC-cultures. Biochim. Biophys. Acta, 1783, 347-359.
23. Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S.W. et al. (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell, 87, 493-506.
24. Apostol, B.L., Illes, K., Pallos, J., Bodai, L., Wu, J., Strand, A., Schweitzer, E.S., Olson, J.M., Kazantsev, A., Marsh, J.L. et al. (2006) Mutant huntingtin altersMAPKsignaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum. Mol. Genet., 15, 273-285.
25. Colin, E., Regulier, E., Perrin, V., Durr, A., Brice, A., Aebischer, P., Deglon, N., Humbert, S. and Saudou, F. (2005) Akt is altered in an animal model of Huntington's disease and in patients. Eur. J. Neurosci., 21, 1478-1488.
26. Varma, H., Yamamoto, A., Sarantos, M.R., Hughes, R.E. and Stockwell, B.R. (2010) Mutant huntingtin alters cell fate in response to microtubule depolymerization via the GEF-H1-RhoA-ERK pathway. J. Biol. Chem., 285, 37445-37457.
27. Quarles, R.H. (2007) Myelin-associated glycoprotein (MAG): past, present and beyond. J. Neurochem., 100, 1431-1448.
28. Arrasate, M. and Finkbeiner, S. (2012) Protein aggregates in Huntington's disease. Exp. Neurol., 238, 1-11.
29. Cepeda, C., Starling, A.J., Wu, N., Nguyen, O.K., Uzgil, B., Soda, T., Andre, V.M., Ariano, M.A. and Levine, M.S. (2004) IncreasedGABAergic function in mouse models of Huntington's disease: reversal by BDNF. J. Neurosci. Res., 78, 855-867.
30. Lahiri, S., Park, H., Laviad, E.L., Lu, X., Bittman, R. and Futerman, A.H. (2009) Ceramide synthesis is modulated by the sphingosine analog FTY720 via a mixture of uncompetitive and noncompetitive inhibition in an Acyl-CoA chain length-dependent manner. J. Biol. Chem., 284, 16090-16098.
31. Di Pardo, A., Maglione, V., Alpaugh, M., Horkey, M., Atwal, R.S., Sassone, J., Ciammola, A., Steffan, J.S., Fouad, K., Truant, R. et al. (2012) Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc. Natl Acad. Sci. USA, 109, 3528-3533.
32. Gu, X., Greiner, E.R., Mishra, R., Kodali, R., Osmand, A., Finkbeiner, S., Steffan, J.S., Thompson, L.M., Wetzel, R. and Yang, X.W. (2009) Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron, 64, 828-840.
33. Atwal, R.S., Desmond, C.R., Caron, N., Maiuri, T., Xia, J., Sipione, S. and Truant, R. (2011) Kinase inhibitors modulate huntingtin cell localization and toxicity. Nat. Chem. Biol., 7, 453-460.
34. Suzuki, S., Enosawa, S., Kakefuda, T., Shinomiya, T., Amari, M., Naoe, S., Hoshino, Y. and Chiba, K. (1996) A novel immunosuppressant, FTY720, with a unique mechanismof action, induces long-term graft acceptance in rat and dog allotransplantation. Transplantation, 61, 200-205.
35. Hemmati, F., Dargahi, L., Nasoohi, S., Omidbakhsh, R., Mohamed, Z., Chik, Z., Naidu, M. and Ahmadiani, A. (2013) Neurorestorative effect of FTY720 in a rat model of Alz'eimer's disease: Comparison with Memantine. Behav. Brain Res., 252C, 415-421.
36. Humbert, S., Bryson, E.A., Cordelieres, F.P., Connors, N.C., Datta, S.R., Finkbeiner, S., Greenberg, M.E. and Saudou, F. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev. Cell, 2, 831-837.
37. Bodai, L. and Marsh, J.L. (2012) A novel target for Huntington's disease: ERK at the crossroads of signaling. The ERK signaling pathway is implicated in Huntington's disease and its upregulation ameliorates pathology. Bioessays, 34, 142-148.
38. Sarantos, M.R., Papanikolaou, T., Ellerby, L.M. and Hughes, R.E. (2012) Pizotifen activates ERK and provides neuroprotection in vitro and in vivo in models of Huntington's disease. J. Huntingtons Dis., 1, 195-210.
39. Bibb, J.A., Yan, Z., Svenningsson, P., Snyder, G.L., Pieribone, V.A., Horiuchi, A., Nairn, A.C., Messer, A. and Greengard, P. (2000) Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice. Proc. Natl Acad. Sci. USA, 97, 6809-6814.
40. Foster, C.A., Howard, L.M., Schweitzer, A., Persohn, E., Hiestand, P.C., Balatoni, B., Reuschel, R., Beerli, C., Schwartz, M. and Billich, A. (2007) Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J. Pharmacol. Exp. Ther., 323, 469-475.
41. Kim, H.J., Miron, V.E., Dukala, D., Proia, R.L., Ludwin, S.K., Traka, M., Antel, J.P. and Soliven, B. (2011) Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model. FASEB J., 25, 1509-1518.
42. Carroll, J.B., Lerch, J.P., Franciosi, S., Spreeuw, A., Bissada, N., Henkelman, R.M. and Hayden, M.R. (2011) Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease. Neurobiol. Dis., 43, 257-265.
43. Xiang, Z., Valenza, M., Cui, L., Leoni, V., Jeong, H.K., Brilli, E., Zhang, J., Peng, Q., Duan, W., Reeves, S.A. et al. (2011) Peroxisome-proliferator-activated receptor gamma coactivator 1 alpha contributes to dysmyelination in experimental models of Huntington's disease. J. Neurosci., 31, 9544-9553.
44. Aboul-Enein, F., Rauschka, H., Kornek, B., Stadelmann, C., Stefferl, A., Bruck, W., Lucchinetti, C., Schmidbauer, M., Jellinger, K. and Lassmann, H. (2003) Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J. Neuropathol. Exp. Neurol., 62, 25-33.
45. Lopez, P.H., Ahmad, A.S., Mehta, N.R., Toner, M., Rowland, E.A., Zhang, J., Dore, S. and Schnaar, R.L. (2011) Myelin-associated glycoprotein protects neurons from excitotoxicity. J. Neurochem., 116, 900-908.
46. Nguyen, T., Mehta, N.R., Conant, K., Kim, K.J., Jones, M., Calabresi, P.A., Melli, G., Hoke, A., Schnaar, R.L., Ming, G.L. et al. (2009) Axonal protective effects of the myelin-associated glycoprotein. J. Neurosci., 29, 630-637.
47. Bogush, A., Pedrini, S., Pelta-Heller, J., Chan, T., Yang, Q., Mao, Z., Sluzas, E., Gieringer, T. and Ehrlich, M.E. (2007) AKT and CDK5/p35 mediate brain-derived neurotrophic factor induction of DARPP-32 in medium size spiny neurons in vitro. J. Biol. Chem., 282, 7352-7359.
48. VonDran, M.W., Singh, H., Honeywell, J.Z. and Dreyfus, C.F. (2011) Levels ofBDNFimpact oligodendrocyte lineage cells following a cuprizone lesion. J. Neurosci., 31, 14182-14190.
49. Binder, D.K. and Scharfman, H.E. (2004) Brain-derived neurotrophic factor. Growth Factors, 22, 123-131.
50. Gauthier, L.R., Charrin, B.C., Borrell-pages, M., Dompierre, J.P., Rangone, H., Cordelieres, F.P., De Mey, J., MacDonald, M.E., Lessmann, V., Humbert, S. et al. (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell, 118, 127-138.
51. Xie, Y., Hayden, M.R. and Xu, B. (2010) BDNF overexpression in the forebrain rescues Huntington's disease phenotypes in YAC128 mice. J. Neurosci., 30, 14708-14718.
52. Giralt, A., Carreton, O., Lao-Peregrin, C., Martin, E.D. and Alberch, J. (2011) Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction. Mol. Neurodegener., 6, 71.
53. Cummings, D.M., Andre, V.M., Uzgil, B.O., Gee, S.M., Fisher, Y.E., Cepeda, C. and Levine, M.S. (2009) Alterations in cortical excitation and inhibition in genetic mouse models of Huntington's disease. J. Neurosci., 29, 10371-10386.
54. Arrasate, M., Mitra, S., Schweitzer, E.S., Segal, M.R. and Finkbeiner, S. (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature, 431, 805-810.
55. Sanchez, I., Mahlke, C. and Yuan, J. (2003) Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature, 421, 373-379.
56. Payne, S.G., Oskeritzian, C.A., Griffiths, R., Subramanian, P., Barbour, S.E., Chalfant, C.E., Milstien, S. and Spiegel, S. (2007) The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood, 109, 1077-1785.
57. Caron, N.S., Desmond, C.R., Xia, J. and Truant, R. (2013) Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin. Proc. Natl Acad. Sci. USA, 110, 14610-14615.
58. Mishra, R., Hoop, C.L., Kodali, R., Sahoo, B., van der Wel, P.C. and Wetzel, R. (2012) Serine phosphorylation suppresses huntingtin amyloid accumulation by altering protein aggregation properties. J. Mol. Biol., 424, 1-14.
59. Thompson, L.M., Aiken, C.T., Kaltenbach, L.S., Agrawal, N., Illes, K., Khoshnan, A., Martinez-Vincente, M., Arrasate, M., O'Rourke, J.G., Khashwji, H. et al. (2009) IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J. Cell. Biol., 187, 1083-1099.
60. Benn, C.L., Landles, C., Li, H., Strand, A.D., Woodman, B., Sathasivam, K., Li, S.H., Ghazi-Noori, S., Hockly, E., Faruque, S.M. et al. (2005)Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease. Hum. Mol. Genet., 14, 3065-3078.
61. Ontaneda, D., Hara-Cleaver, C., Rudick, R.A., Cohen, J.A. and Bermel, R.A. (2012) Early tolerability and safety of fingolimod in clinical practice. J. Neurol. Sci., 323, 167-172.
62. Bancroft, G.J. and Gamble, M. (2008) Theory and Using Fresh Solutions. Regarding H&E Staining, Formalin Pigment Practice of Histological Techniques. Churchill Livingstone, Edinburgh.
63. Li, H., Li, S.H., Yu, Z.X., Shelbourne, P. and Li, X.J. (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. J. Neurosci., 21, 8473-8481.