A potent and selective sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of huntington's disease

Human Molecular Genetics

Volumn 23, Issue 11, 2014, Pages 2995-3007

  Smith, Marianne R ^a   Syed, Adeela ^a   Lukacsovich, Tamas ^a   Purcell, Judy ^a   Barbaro, Brett A ^a   Worthge, Shane A ^a   Wei, Stephen R ^a   Pollio, Giuseppe ^b   Magnoni, Letizia ^b   Scali, Carla ^b   Massai, Luisa ^b   Franceschini, Davide ^b   Camarri, Michela ^b   Gianfriddo, Marco ^b,g   Diodato, Enrica ^b   Thomas, Russell ^b   Gokce, Ozgun ^e,h   Tabrizi, S J ^d   Caricasole, Andrea ^b,i   Landwehrmeyer, Bernard ^f   Menalled, Liliana ^c   Murphy, Carol ^c   Ramboz, Sylvie ^c   Luthi Carter, Ruth ^e,j   Westerberg, Goran ^b,k   Marsh, J Lawrence ^a   more..

^a UNIVERSITY OF CALIFORNIA   (United States)

^b Siena Biotech SpA   (Italy)

^c PSYCHOGENICS INC   (United States)

^d UNIVERSITY COLLEGE LONDON   (United Kingdom)

^e EPFL   (Switzerland)

^f UNIVERSITY OF ULM   (Germany)

^g Worldwide Clinical Trials   (Italy)

^h STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

ⁱ IRBM   (Italy)

^j UNIVERSITY OF LEICESTER   (United Kingdom)

^k La Crocina   (Italy)

more..

Author keywords

[No Author keywords available]

Indexed keywords

HUNTINGTIN; PROTEIN INHIBITOR; SELISISTAT; SIRTUIN 1; SIRTUIN 1 INHIBITOR; SIRTUIN 2; UNCLASSIFIED DRUG; 6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-CARBOXAMIDE; CARBAZOLE DERIVATIVE; DROSOPHILA PROTEIN; ENZYME INHIBITOR; HISTONE DEACETYLASE; SIR2 PROTEIN, DROSOPHILA; SIRTUIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DROSOPHILA; DROSOPHILA MELANOGASTER; DRUG EFFECT; FEMALE; HUNTINGTON CHOREA; MAMMAL; MOUSE; MOUSE MODEL; NONHUMAN; PRIORITY JOURNAL; ANIMAL; ANTAGONISTS AND INHIBITORS; C57BL MOUSE; DISEASE MODEL; DRUG EFFECTS; ENZYMOLOGY; GENETICS; HUMAN; HUNTINGTON DISEASE; MALE; METABOLISM; PATHOLOGY; PC12 CELL LINE; RAT; SPRAGUE DAWLEY RAT;

ANIMALS; CARBAZOLES; DISEASE MODELS, ANIMAL; DROSOPHILA MELANOGASTER; DROSOPHILA PROTEINS; ENZYME INHIBITORS; FEMALE; HISTONE DEACETYLASES; HUMANS; HUNTINGTON DISEASE; MALE; MICE; MICE, INBRED C57BL; PC12 CELLS; RATS; RATS, SPRAGUE-DAWLEY; SIRTUIN 1; SIRTUINS;

EID: 84899965665     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddu010     Document Type: Article

References (45)

1. Benn, C.L., Sun, T., Sadri-Vakili, G., McFarland, K.N., DiRocco, D.P., Yohrling, G.J., Clark, T.W., Bouzou, B. and Cha, J.H. (2008) Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J. Neurosci., 28, 10720-10733.
2. Cha, J.H. (2000) Transcriptional dysregulation in Huntington's disease. Trends Neurosci., 23, 387-392.
3. McFarland, K.N., Das, S., Sun, T.T., Leyfer, D., Xia, E., Sangrey, G.R., Kuhn, A., Luthi-Carter, R., Clark, T.W., Sadri-Vakili, G. et al. (2012) Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington's disease. PLoS ONE, 7, e41423.
4. Ferrante, R.J., Kubilus, J.K., Lee, J., Ryu, H., Beesen, A., Zucker, B., Smith, K., Kowall, N.W., Ratan, R.R., Luthi-Carter, R. et al. (2003) Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J. Neurosci., 23, 9418-9427.
5. Sadri-Vakili, G. and Cha, J.H. (2006) Mechanisms of disease: Histone modifications in Huntington's disease. Nat. Clin. Pract. Neurol., 2, 330-338.
6. Steffan, J.S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B.L., Kazantsev, A., Schmidt, E., Zhu, Y.Z., Greenwald, M. et al. (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature, 413, 739-743.
7. McLaughlin, F. and La Thangue, N.B. (2004) Histone deacetylase inhibitors open new doors in cancer therapy. Biochem. Pharmacol., 68, 1139-1144.
8. Dali-Youcef, N., Lagouge, M., Froelich, S., Koehl, C., Schoonjans, K. and Auwerx, J. (2007) Sirtuins: the 'magnificent seven', function, metabolism and longevity. Ann. Med., 39, 335-345.
9. Pallos, J., Bodai, L., Lukacsovich, T., Purcell, J.M., Steffan, J.S., Thompson, L.M. and Marsh, J.L. (2008) Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington's disease. Hum. Mol. Genet., 17, 3767-3775.
10. Li, Y., Xu, W., McBurney, M.W. and Longo, V.D. (2008) SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab., 8, 38-48.
11. Ghosh, S. and Feany, M.B. (2004) Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases. Hum. Mol. Genet., 13, 2011-2018.
12. Green, K.N., Steffan, J.S., Martinez-Coria, H., Sun, X., Schreiber, S.S., Thompson, L.M. and LaFerla, F.M. (2008) Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J. Neurosci., 28, 11500-11510.
13. Grubisha, O., Smith, B.C. and Denu, J.M. (2005) Small molecule regulation of Sir2 protein deacetylases. FEBS J., 272, 4607-4616.
14. Napper, A.D., Hixon, J., McDonagh, T., Keavey, K., Pons, J.F., Barker, J., Yau, W.T., Amouzegh, P., Flegg, A., Hamelin, E. et al. (2005) Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J. Med. Chem., 48, 8045-8054.
15. Sauve, A.A., Moir, R.D., Schramm, V.L. and Willis, I.M. (2005) Chemical activation of Sir2-dependent silencing by relief of nicotinamide inhibition. Mol. Cell, 17, 595-601.
16. Grozinger, C.M., Chao, E.D., Blackwell, H.E., Moazed, D. and Schreiber, S.L. (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem., 276, 38837-38843.
17. Mai, A., Massa, S., Lavu, S., Pezzi, R., Simeoni, S., Ragno, R., Mariotti, F.R., Chiani, F., Camilloni, G. and Sinclair, D.A. (2005) Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J. Med. Chem., 48, 7789-7795.
18. Gey, C., Kyrylenko, S., Hennig, L., Nguyen, L.H., Buttner, A., Pham, H.D. and Giannis, A. (2007) Phloroglucinol derivatives guttiferone G, aristoforin, and hyperforin: inhibitors of human sirtuins SIRT1 and SIRT2. Angew. Chem., 46, 5219-5222.
19. Zhao, X., Allison, D., Condon, B., Zhang, F., Gheyi, T., Zhang, A., Ashok, S., Russell, M., MacEwan, I., Qian, Y. et al. (2013) The 2.5Acrystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition. J. Med. Chem., 56, 963-969.
20. Gertz, M., Fischer, F., Nguyen, G.T.,Lakshminarasimhan, M., Schutkowski, M., Weyand, M. and Steegborn, C. (2013) Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism. Proc. Natl. Acad. Sci. USA, 110, E2772-e42781.
21. Song, W., Smith, M.R., Syed, A., Lukacsovich, T., Barbaro, B.A., Purcell, J., Bornemann, D.J., Burke, J. and Marsh, J.L. (2013) Morphometric analysis of Huntington's disease neurodegeneration in Drosophila. Methods Mol. Biol., 1017, 41-57.
22. Marsh, J.L. and Thompson, L.M. (2006) Drosophila in the study of neurodegenerative disease. Neuron, 52, 169-178.
23. Rothgiesser, K.M., Erener, S., Waibel, S., Luscher, B. and Hottiger, M.O. (2010) SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J. Cell Sci., 123, 4251-4258.
24. Wyttenbach, A., Swartz, J., Kita, H., Thykjaer, T., Carmichael, J., Bradley, J., Brown, R., Maxwell, M., Schapira, A., Orntoft, T.F. et al. (2001) Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease. Hum. Mol. Genet., 10, 1829-1845.
25. Perrin, V., Regulier, E., Abbas-Terki, T., Hassig, R., Brouillet, E., Aebischer, P., Luthi-Carter, R. and Deglon, N. (2007) Neuroprotection by Hsp104 and Hsp27 in lentiviral-based rat models of Huntington's disease. Mol. Ther., 15, 903-911.
26. Runne, H., Regulier, E., Kuhn, A., Zala, D., Gokce, O., Perrin, V., Sick, B., Aebischer, P., Deglon, N. and Luthi-Carter, R. (2008) Dysregulation of gene expression in primary neuron models of Huntington's disease shows that polyglutamine-related effects on the striatal transcriptome may not be dependent on brain circuitry. J. Neurosci., 28, 9723-9731.
27. Zala, D., Benchoua, A., Brouillet, E., Perrin, V., Gaillard, M.C., Zurn, A.D., Aebischer, P. and Deglon, N. (2005) Progressive and selective striatal degeneration in primary neuronal cultures using lentiviral vector coding for a mutant huntingtin fragment. Neurobiol. Dis., 20, 785-798.
28. 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.
29. Menalled, L., El-Khodor, B.F., Patry, M., Suarez-Farinas, M., Orenstein, S.J., Zahasky, B., Leahy, C., Wheeler, V., Yang, X.W., MacDonald, M. et al. (2009) Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models. Neurobiol. Dis., 35, 319-336.
30. Menalled, L.B., Patry, M., Ragland, N., Lowden, P.A., Goodman, J., Minnich, J., Zahasky, B., Park, L., Leeds, J., Howland, D. et al. (2010) Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline. PLoS ONE, 5, e9793.
31. Sathasivam, K., Neueder, A., Gipson, T.A., Landles, C., Benjamin, A.C., Bondulich, M.K., Smith, D.L., Faull, R.L., Roos, R.A., Howland, D. et al. (2013) Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc. Natl. Acad. Sci. USA, 110, 2366-2370.
32. Zhang, T. and Kraus, W.L. (2010) SIRT1-dependent regulation of chromatin and transcription: linking NAD(+) metabolism and signaling to the control of cellular functions. Biochim. Biophys. Acta, 1804, 1666-1675.
33. Vaquero, A., Scher, M., Lee, D., Erdjument-Bromage, H., Tempst, P. and Reinberg, D. (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell, 16, 93-105.
34. Vaziri, H., Dessain, S.K., Ng Eaton, E., Imai, S.I., Frye, R.A., Pandita, T.K., Guarente, L. and Weinberg, R.A. (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell, 107, 149-159.
35. Motta, M.C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M. and Guarente, L. (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell, 116, 551-563.
36. Yang, Y., Hou, H., Haller, E.M., Nicosia, S.V. and Bai, W. (2005) Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J., 24, 1021-1032.
37. Yeung, F., Hoberg, J.E., Ramsey, C.S., Keller, M.D., Jones, D.R., Frye, R.A. and Mayo, M.W. (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J., 23, 2369-2380.
38. Nemoto, S., Fergusson, M.M. and Finkel, T. (2005) SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J. Biol. Chem., 280, 16456-16460.
39. Bouras, T., Fu, M., Sauve, A.A., Wang, F., Quong, A.A., Perkins, N.D., Hay, R.T., Gu, W. and Pestell, R.G. (2005) SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J. Biol. Chem., 280, 10264-10276.
40. Branco, J., Al-Ramahi, I., Ukani, L., Perez, A.M., Fernandez-Funez, P., Rincon-Limas, D. and Botas, J. (2008) Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases. Hum. Mol. Genet., 17, 376-390.
41. Jeong, H., Cohen, D.E., Cui, L., Supinski, A., Savas, J.N., Mazzulli, J.R., Yates, J.R. 3rd, Bordone, L., Guarente, L. and Krainc, D. (2012) Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat. Med., 18, 159-165.
42. Jiang, M., Wang, J., Fu, J., Du, L., Jeong, H., West, T., Xiang, L., Peng, Q., Hou, Z., Cai, H. et al. (2012) Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat. Med., 18, 153-158.
43. Kakefuda, K., Fujita, Y., Oyagi, A., Hyakkoku, K., Kojima, T., Umemura, K., Tsuruma, K., Shimazawa, M., Ito, M., Nozawa, Y. et al. (2009) Sirtuin 1 overexpression mice show a reference memory deficit, but not neuroprotection. Biochem. Biophys. Res. Commun., 387, 784-788.
44. Griswold, A.J., Chang, K.T., Runko, A.P., Knight, M.A. and Min, K.T. (2008) Sir2 mediates apoptosis through JNK-dependent pathways in Drosophila. Proc. Natl. Acad. Sci. USA, 105, 8673-8678.
45. Wang, J. and Chen, J. (2010) SIRT1 regulates autoacetylation and histone acetyltransferase activity of TIP60. J. Biol. Chem., 285, 11458-11464.