Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterised by motor and non-motor symptoms, resulting from the degeneration of nigrostriatal dopaminergic neurons and peripheral autonomic neurons. Given the limited success of neurotrophic factors in clinical trials, there is a need to identify new small molecule drugs and drug targets to develop novel therapeutic strategies to protect all neurons that degenerate in PD. Epigenetic dysregulation has been implicated in neurodegenerative disorders, while targeting histone acetylation is a promising therapeutic avenue for PD. We and others have demonstrated that histone deacetylase inhibitors have neurotrophic effects in experimental models of PD. Activators of histone acetyltransferases (HAT) provide an alternative approach for the selective activation of gene expression, however little is known about the potential of HAT activators as drug therapies for PD. To explore this potential, the present study investigated the neurotrophic effects of CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), which is a potent small molecule activator of the histone acetyltransferase p300/CBP, in the SH-SY5Y neuronal cell line. We report that CTPB promoted the survival and neurite growth of the SH-SY5Y cells, and also protected these cells from cell death induced by the neurotoxin 6-hydroxydopamine. This study is the first to investigate the phenotypic effects of the HAT activator CTPB, and to demonstrate that p300/CBP HAT activation has neurotrophic effects in a cellular model of PD.
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Abbreviations
- 6-OHDA:
-
6-Hydroxydopamine
- BMP:
-
Bone morphogenetic protein(s)
- CTPB:
-
N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide
- DA:
-
Dopaminergic/dopamine
- DAPI:
-
4′-6-Diamidino-2-phenylindole
- DMSO:
-
Dimethyl sulfoxide
- DIV:
-
Day(s) in vitro
- H3:
-
Total histone H3
- HAT:
-
Histone acetyltransferase(s)
- HDAC:
-
Histone deacetylase(s)
- LDH:
-
Lactate dehydrogenase
- MTT:
-
Thiazolyl blue tetrazolium bromide
- N:
-
Number of repetitions
- pAcH3:
-
p-Acetylated-histone H3
- PBS-T:
-
10 mM PBS containing 0.02 % Triton X-100
- PD:
-
Parkinson’s disease
- SNpc:
-
Substantia nigra pars compacta
References
Abel T, Zukin RS (2008) Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Curr Opin Pharmacol 8:57–64. doi:10.1016/j.coph.2007.12.002
Allfrey VG, Faulkner R, Mirsky AE (1964) Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci USA 51:786–794
Balasubramanyam K, Swaminathan V, Ranganathan A, Kundu TK (2003) Small molecule modulators of histone acetyltransferase p300. J Biol Chem 278:19134–19140. doi:10.1074/jbc.M301580200
Bedard C, Wallman MJ, Pourcher E, Gould PV, Parent A, Parent M (2011) Serotonin and dopamine striatal innervation in Parkinson’s disease and Huntington’s chorea. Parkinsonism Relat Disord 17:593–598. doi:10.1016/j.parkreldis.2011.05.012
Bethlem J, Den Hartog Jager WA (1960) The incidence and characteristics of Lewy bodies in idiopathic paralysis agitans (Parkinson’s disease). J Neurol Neurosurg Psychiatry 23:74–80
Chatterjee S et al (2013) A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice. J Neurosci 33:10698–10712. doi:10.1523/JNEUROSCI.5772-12.2013
Chen PS et al (2006) Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 11:1116–1125. doi:10.1038/sj.mp.4001893
Chen PS et al (2007) Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 149:203–212. doi:10.1016/j.neuroscience.2007.06.053
Chen YL, Monteith N, Law PY, Loh HH (2010) Dynamic association of p300 with the promoter of the G protein-coupled rat delta opioid receptor gene during NGF-induced neuronal differentiation. Biochem Biophys Res Commun 396:294–298. doi:10.1016/j.bbrc.2010.04.083
Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CT (2009) Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 32:591–601. doi:10.1016/j.tins.2009.06.002
Collins LM, Adriaanse LJ, Theratile SD, Hegarty SV, Sullivan AM, O’Keeffe GW (2015) Class-IIa histone deacetylase inhibition promotes the growth of neural processes and protects them against neurotoxic insult. Mol Neurobiol 51:1432–1442. doi:10.1007/s12035-014-8820-8
Cong SY, Pepers BA, Evert BO, Rubinsztein DC, Roos RA, van Ommen GJ, Dorsman JC (2005) Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. Mol Cell Neurosci 30:560–571
Crampton SJ, Collins LM, Toulouse A, Nolan YM, O’Keeffe GW (2012) Exposure of foetal neural progenitor cells to IL-1beta impairs their proliferation and alters their differentiation—a role for maternal inflammation? J Neurochem 120:964–973. doi:10.1111/j.1471-4159.2011.07634.x
Culmsee C et al (2003) Reciprocal inhibition of p53 and nuclear factor-kappaB transcriptional activities determines cell survival or death in neurons. J Neurosci 23:8586–8595
Davies AM (2009) Extracellular signals regulating sympathetic neuron survival and target innervation during development. Auton Neurosci 151:39–45. doi:10.1016/j.autneu.2009.07.011
Devipriya B, Kumaradhas P (2013) Charge density distribution and the electrostatic moments of CTPB in the active site of p300 enzyme: a DFT and charge density study. J Theor Biol 335:119–129. doi:10.1016/j.jtbi.2013.06.001
Devipriya B, Parameswari AR, Rajalakshmi G, Palvannan T, Kumaradhas P (2010) Exploring the binding affinities of p300 enzyme activators CTPB and CTB using docking method. Indian J Biochem Biophys 47:364–369
Dorsey ER, George BP, Leff B, Willis AW (2013) The coming crisis: obtaining care for the growing burden of neurodegenerative conditions. Neurology 80:1989–1996. doi:10.1212/WNL.0b013e318293e2ce
Gardian G, Yang L, Cleren C, Calingasan NY, Klivenyi P, Beal MF (2004) Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity. NeuroMol Med 5:235–241. doi:10.1385/NMM:5:3:235
Gaub P, Tedeschi A, Puttagunta R, Nguyen T, Schmandke A, Di Giovanni S (2010) HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. Cell Death Differ 17:1392–1408. doi:10.1038/cdd.2009.216
Gaub P, Joshi Y, Wuttke A, Naumann U, Schnichels S, Heiduschka P, Di Giovanni S (2011) The histone acetyltransferase p300 promotes intrinsic axonal regeneration. Brain 134:2134–2148. doi:10.1093/brain/awr142
Glebova NO, Ginty DD (2005) Growth and survival signals controlling sympathetic nervous system development. Annu Rev Neurosci 28:191–222. doi:10.1146/annurev.neuro.28.061604.135659
Goldstein DS, Holmes C, Cannon RO 3rd, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336:696–702. doi:10.1056/NEJM199703063361004
Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO 3rd (2000) Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133:338–347
Gomez-Santos C, Ambrosio S, Ventura F, Ferrer I, Reiriz J (2002) TGF-beta1 increases tyrosine hydroxylase expression by a mechanism blocked by BMP-2 in human neuroblastoma SH-SY5Y cells. Brain Res 958:152–160
Gutierrez H, Hale VA, Dolcet X, Davies A (2005) NF-kappaB signalling regulates the growth of neural processes in the developing PNS and CNS. Development 132:1713–1726. doi:10.1242/dev.01702
Gutierrez H, O’Keeffe GW, Gavalda N, Gallagher D, Davies AM (2008) Nuclear factor kappa B signaling either stimulates or inhibits neurite growth depending on the phosphorylation status of p65/RelA. J Neurosci 28:8246–8256. doi:10.1523/JNEUROSCI.1941-08.2008
Habash T, Saleh A, Roy Chowdhury SK, Smith DR, Fernyhough P (2015) The proinflammatory cytokine, interleukin-17A, augments mitochondrial function and neurite outgrowth of cultured adult sensory neurons derived from normal and diabetic rats. Exp Neurol 273:177–189. doi:10.1016/j.expneurol.2015.08.016
Hahnen E, Hauke J, Trankle C, Eyupoglu IY, Wirth B, Blumcke I (2008) Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin Investig Drugs 17:169–184. doi:10.1517/13543784.17.2.169
Harrison IF, Dexter DT (2013) Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson’s disease? Pharmacol Ther 140:34–52. doi:10.1016/j.pharmthera.2013.05.010
Hegarty SV, Sullivan AM, O’Keeffe GW (2013) BMP2 and GDF5 induce neuronal differentiation through a Smad dependant pathway in a model of human midbrain dopaminergic neurons. Mol Cell Neurosci 56C:263–271. doi:10.1016/j.mcn.2013.06.006
Hegarty SV, Collins LM, Gavin AM, Roche SL, Wyatt SL, Sullivan AM, O’Keeffe GW (2014a) Canonical BMP-Smad signalling promotes neurite growth in rat midbrain dopaminergic neurons. NeuroMol Med 16:473–489. doi:10.1007/s12017-014-8299-5
Hegarty SV, O’Keeffe GW, Sullivan AM (2014b) Neurotrophic factors: from neurodevelopmental regulators to novel therapies for Parkinson’s disease. Neural Regen Res 9:1708–1711. doi:10.4103/1673-5374.143410
Hodges A et al (2006) Regional and cellular gene expression changes in human Huntington’s disease brain. Hum Mol Genet 15:965–977. doi:10.1093/hmg/ddl013
Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376. doi:10.1136/jnnp.2007.131045
Jellinger KA (1991) Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 14:153–197
Jellinger KA (2012) Neuropathology of sporadic Parkinson’s disease: evaluation and changes of concepts. Mov Disord 27:8–30. doi:10.1002/mds.23795
Jiang Y et al (2008) Epigenetics in the nervous system. J Neurosci 28:11753–11759. doi:10.1523/JNEUROSCI.3797-08.2008
Jin H, Kanthasamy A, Ghosh A, Yang Y, Anantharam V, Kanthasamy AG (2011) alpha-Synuclein negatively regulates protein kinase Cdelta expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. J Neurosci 31:2035–2051. doi:10.1523/JNEUROSCI.5634-10.2011
Kaufmann H, Goldstein DS (2013) Autonomic dysfunction in Parkinson disease. Handb Clin Neurol 117:259–278. doi:10.1016/B978-0-444-53491-0.00021-3
Kazantsev AG, Thompson LM (2008) Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 7:854–868. doi:10.1038/nrd2681
Kidd SK, Schneider JS (2010) Protection of dopaminergic cells from MPP + -mediated toxicity by histone deacetylase inhibition. Brain Res 1354:172–178. doi:10.1016/j.brainres.2010.07.041
Kidd SK, Schneider JS (2011) Protective effects of valproic acid on the nigrostriatal dopamine system in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience 194:189–194. doi:10.1016/j.neuroscience.2011.08.010
Kontopoulos E, Parvin JD, Feany MB (2006) Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15:3012–3023. doi:10.1093/hmg/ddl243
Koyano-Nakagawa N, Wettstein D, Kintner C (1999) Activation of Xenopus genes required for lateral inhibition and neuronal differentiation during primary neurogenesis. Mol Cell Neurosci 14:327–339. doi:10.1006/mcne.1999.0783
Lee S, Lee B, Lee JW, Lee SK (2009) Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP. Neuron 62:641–654. doi:10.1016/j.neuron.2009.04.025
Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066. doi:10.1016/S0140-6736(09)60492-X
Lopez-Atalaya JP, Valor LM, Barco A (2014) Epigenetic factors in intellectual disability: the Rubinstein–Taybi syndrome as a paradigm of neurodevelopmental disorder with epigenetic origin. Prog Mol Biol Transl Sci 128:139–176. doi:10.1016/B978-0-12-800977-2.00006-1
Lucio CG, Vincenzo C, Antonio R, Oscar T, Luigi M (2013) Neurological applications for myocardial MIBG scintigraphy. Nucl Med Rev Cent East Eur 16:35–41. doi:10.5603/NMR.2013.0007
Mantelingu K et al (2007) Activation of p300 histone acetyltransferase by small molecules altering enzyme structure: probed by surface-enhanced Raman spectroscopy. J Phys Chem B 111:4527–4534. doi:10.1021/jp067655s
Mayhew TM (1992) A review of recent advances in stereology for quantifying neural structure. J Neurocytol 21:313–328
McMillan CR, Sharma R, Ottenhof T, Niles LP (2007) Modulation of tyrosine hydroxylase expression by melatonin in human SH-SY5Y neuroblastoma cells. Neurosci Lett 419:202–206. doi:10.1016/j.neulet.2007.04.029
Morikawa Y, Dai YS, Hao J, Bonin C, Hwang S, Cserjesi P (2005) The basic helix-loop-helix factor Hand 2 regulates autonomic nervous system development. Dev Dyn 234:613–621. doi:10.1002/dvdy.20544
O’Keeffe GW et al (2016) Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation. Neural Dev 11:4. doi:10.1186/s13064-016-0060-3
Olanow CW et al (2015) Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: a double-blind, randomized, controlled trial. Ann Neurol 78:248–257. doi:10.1002/ana.24436
Outeiro TF et al (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317:516–519. doi:10.1126/science.1143780
Pearson KL, Hunter T, Janknecht R (1999) Activation of Smad1-mediated transcription by p300/CBP. Biochim Biophys Acta 1489:354–364
Presgraves SP, Ahmed T, Borwege S, Joyce JN (2004) Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists. Neurotox Res 5:579–598
Rouaux C, Jokic N, Mbebi C, Boutillier S, Loeffler JP, Boutillier AL (2003) Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration. EMBO J 22:6537–6549. doi:10.1093/emboj/cdg615
Saha RN, Pahan K (2006) HATs and HDACs in neurodegeneration: a tale of disconcerted acetylation homeostasis. Cell Death Differ 13:539–550. doi:10.1038/sj.cdd.4401769
Schneider A et al (2013) Acetyltransferases (HATs) as targets for neurological therapeutics. Neurotherapeutics 10:568–588. doi:10.1007/s13311-013-0204-7
Selvi BR et al (2008) Intrinsically fluorescent carbon nanospheres as a nuclear targeting vector: delivery of membrane-impermeable molecule to modulate gene expression in vivo. Nano Lett 8:3182–3188. doi:10.1021/nl801503m
Seo S et al (2012) Kruppel-like factor 11 differentially couples to histone acetyltransferase and histone methyltransferase chromatin remodeling pathways to transcriptionally regulate dopamine D2 receptor in neuronal cells. J Biol Chem 287:12723–12735. doi:10.1074/jbc.M112.351395
Serrano L, Vazquez BN, Tischfield J (2013) Chromatin structure, pluripotency and differentiation. Exp Biol Med (Maywood) 238:259–270. doi:10.1177/1535370213480718
Sheikh BN (2014) Crafting the brain—role of histone acetyltransferases in neural development and disease. Cell Tissue Res 356:553–573. doi:10.1007/s00441-014-1835-7
Souto JA, Conte M, Alvarez R, Nebbioso A, Carafa V, Altucci L, de Lera AR (2008) Synthesis of benzamides related to anacardic acid and their histone acetyltransferase (HAT) inhibitory activities. ChemMedChem 3:1435–1442. doi:10.1002/cmdc.200800096
Souto JA, Benedetti R, Otto K, Miceli M, Alvarez R, Altucci L, de Lera AR (2010) New anacardic acid-inspired benzamides: histone lysine acetyltransferase activators. ChemMedChem 5:1530–1540. doi:10.1002/cmdc.201000158
St Laurent R, O’Brien LM, Ahmad ST (2013) Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson’s disease. Neuroscience 246:382–390. doi:10.1016/j.neuroscience.2013.04.037
Steketee MB, Moysidis SN, Weinstein JE, Kreymerman A, Silva JP, Iqbal S, Goldberg JL (2012) Mitochondrial dynamics regulate growth cone motility, guidance, and neurite growth rate in perinatal retinal ganglion cells in vitro. Invest Ophthalmol Vis Sci 53:7402–7411. doi:10.1167/iovs.12-10298
Sun Y et al (2001) Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104:365–376
Tanaka Y, Naruse I, Hongo T, Xu M, Nakahata T, Maekawa T, Ishii S (2000) Extensive brain hemorrhage and embryonic lethality in a mouse null mutant of CREB-binding protein. Mech Dev 95:133–145
Tao K, Matsuki N, Koyama R (2014) AMP-activated protein kinase mediates activity-dependent axon branching by recruiting mitochondria to axon. Dev Neurobiol 74:557–573. doi:10.1002/dneu.22149
Toulouse A, Collins GC, Sullivan AM (2012) Neurotrophic effects of growth/differentiation factor 5 in a neuronal cell line. Neurotox Res 21:256–265. doi:10.1007/s12640-011-9266-7
Tsui D, Voronova A, Gallagher D, Kaplan DR, Miller FD, Wang J (2014) CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development. Dev Biol 385:230–241. doi:10.1016/j.ydbio.2013.11.005
Valor LM, Viosca J, Lopez-Atalaya JP, Barco A (2013) Lysine acetyltransferases CBP and p300 as therapeutic targets in cognitive and neurodegenerative disorders. Curr Pharm Des 19:5051–5064
Wang J et al (2010) CBP histone acetyltransferase activity regulates embryonic neural differentiation in the normal and Rubinstein-Taybi syndrome brain. Dev Cell 18:114–125. doi:10.1016/j.devcel.2009.10.023
Wong K et al (2005) HIV-1 Tat interactions with p300 and PCAF transcriptional coactivators inhibit histone acetylation and neurotrophin signaling through CREB. J Biol Chem 280:9390–9399. doi:10.1074/jbc.M408643200
Wu X et al (2008) Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol 11:1123–1134. doi:10.1017/S1461145708009024
Xie HR, Hu LS, Li GY (2010) SH-SY5Y human neuroblastoma cell line: in vitro cell model of dopaminergic neurons in Parkinson’s disease. Chin Med J (Engl) 123:1086–1092
Yang XJ, Seto E (2007) HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26:5310–5318. doi:10.1038/sj.onc.1210599
Yao TP et al (1998) Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93:361–372
Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G (2001) The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 276:31674–31683. doi:10.1074/jbc.M104309200
Zhu M, Li WW, Lu CZ (2014) Histone decacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection against MPP+. CNS Neurosci Ther 20:308–316. doi:10.1111/cns.12217
Acknowledgments
Studies in the authors’ laboratories are supported by grants from the Irish Research Council (R15897; SVH/AS/G’OK) and the National University of Ireland (R16189; SVH/AS/G’OK).
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Aideen M. Sullivan and Gerard W. O’Keeffe have contributed equally to this work.
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Hegarty, S.V., O’Leary, E., Solger, F. et al. A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease. Neurotox Res 30, 510–520 (2016). https://doi.org/10.1007/s12640-016-9636-2
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DOI: https://doi.org/10.1007/s12640-016-9636-2