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The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

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Neurodegenerative Diseases

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 6))

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Abstract

Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

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Abbreviations

AD:

Alzheimer’s disease

ADME:

Absorption, distribution, metabolism, excretion

ALS:

Amyotrophic lateral sclerosis

BDNF:

Brain-derived neurotrophic factor

CBP:

CREB-binding protein

CNS:

Central nervous system

DNA:

Deoxyribonucleic acid

DRPLA:

Dentatorubral pallidoluysian atrophy

FDA:

Food and Drug Administration

FRDA:

Friedreich’s ataxia

FXN:

Frataxin

GDNF:

Glial cell-derived neurotrophic factor

HAT:

Histone acetylase

HD:

Huntington’s disease

HDAC:

Histone deacetylase

Htt:

Huntingtin

MBG:

Metal-binding group

MEF2:

Myocyte-enhancing factor 2

PD:

Parkinson’s disease

PolyQ:

Polyglutamine

RTS:

Rubenstein–Taybi syndrome

SBMA:

Spinal bulbar muscular atrophy

SCA:

Spinocerebellar ataxia

SUMO:

Small ubiquitin-like modifier

TBP:

TATA-binding protein

UPS:

Ubiquitin–proteosome system

References

  1. Choudhary C et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942):834–840

    CAS  Google Scholar 

  2. Paroni G et al (2004) Caspase-dependent regulation of histone deacetylase 4 nuclear-cytoplasmic shuttling promotes apoptosis. Mol Biol Cell 15(6):2804–2818

    CAS  Google Scholar 

  3. McKinsey TA et al (2000) Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408(6808):106–111

    CAS  Google Scholar 

  4. Glaser KB et al (2003) Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. Mol Cancer Ther 2(2):151–163

    CAS  Google Scholar 

  5. Fischer DD et al (2002) Isolation and characterization of a novel class II histone deacetylase, HDAC10. J Biol Chem 277(8):6656–6666

    CAS  Google Scholar 

  6. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10(1):32–42

    CAS  Google Scholar 

  7. Lahm A et al (2007) Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc Natl Acad Sci USA 104(44):17335–17340

    CAS  Google Scholar 

  8. de Ruijter AJ et al (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370(Pt 3):737–749

    Google Scholar 

  9. Verdin E, Dequiedt F, Kasler HG (2003) Class II histone deacetylases: versatile regulators. Trends Genet 19(5):286–293

    CAS  Google Scholar 

  10. Fischle W et al (2002) Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol Cell 9(1):45–57

    CAS  Google Scholar 

  11. Fischle W et al (1999) A new family of human histone deacetylases related to Saccharomyces cerevisiae HDA1p. J Biol Chem 274(17):11713–11720

    CAS  Google Scholar 

  12. Zhang CL, McKinsey TA, Olson EN (2001) The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc Natl Acad Sci USA 98(13):7354–7359

    CAS  Google Scholar 

  13. Zhang CL et al (2001) Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor. J Biol Chem 276(1):35–39

    CAS  Google Scholar 

  14. Zhao X et al (2005) Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol 25(19):8456–8464

    CAS  Google Scholar 

  15. Nebbioso A et al (2009) Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes. EMBO Rep 10(7):776–782

    CAS  Google Scholar 

  16. Matsuoka H et al (2007) Disruption of HDAC4/N-CoR complex by histone deacetylase inhibitors leads to inhibition of IL-2 gene expression. Biochem Pharmacol 74(3):465–476

    CAS  Google Scholar 

  17. Huang EY et al (2000) Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev 14(1):45–54

    CAS  Google Scholar 

  18. Rajan I et al (2009) Loss of the putative catalytic domain of HDAC4 leads to reduced thermal nociception and seizures while allowing normal bone development. PLoS ONE 4(8):e6612

    Google Scholar 

  19. Vega RB et al (2004) Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119(4):555–566

    CAS  Google Scholar 

  20. Grozinger CM, Schreiber SL (2000) Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc Natl Acad Sci USA 97(14):7835–7840

    CAS  Google Scholar 

  21. Wang AH et al (2000) Regulation of histone deacetylase 4 by binding of 14-3-3 proteins. Mol Cell Biol 20(18):6904–6912

    CAS  Google Scholar 

  22. Broide RS et al (2007) Distribution of histone deacetylases 1-11 in the rat brain. J Mol Neurosci 31(1):47–58

    CAS  Google Scholar 

  23. Kao HY et al (2002) Isolation and characterization of mammalian HDAC10, a novel histone deacetylase. J Biol Chem 277(1):187–193

    CAS  Google Scholar 

  24. Yang XJ, Gregoire S (2005) Class II histone deacetylases: from sequence to function, regulation, and clinical implication. Mol Cell Biol 25(8):2873–2884

    CAS  Google Scholar 

  25. Hubbert C et al (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417(6887):455–458

    CAS  Google Scholar 

  26. Bali P et al (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280(29):26729–26734

    CAS  Google Scholar 

  27. Kovacs JJ et al (2005) HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 18(5):601–607

    CAS  Google Scholar 

  28. Gao L et al (2002) Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J Biol Chem 277(28):25748–25755

    CAS  Google Scholar 

  29. Boyault C et al (2006) HDAC6-p97/VCP controlled polyubiquitin chain turnover. EMBO J 25(14):3357–3366

    CAS  Google Scholar 

  30. Gao J et al (2009) Inactivation of CREB mediated gene transcription by HDAC8 bound protein phosphatase. Biochem Biophys Res Commun 379(1):1–5

    CAS  Google Scholar 

  31. Bertrand P (2010) Inside HDAC with HDAC inhibitors. Eur J Med Chem 45(6):2095–2116

    CAS  Google Scholar 

  32. Glozak MA, Seto E (2009) Acetylation/deacetylation modulates the stability of DNA replication licensing factor Cdt1. J Biol Chem 284(17):11446–11453

    CAS  Google Scholar 

  33. Gantt SL, Gattis SG, Fierke CA (2006) Catalytic activity and inhibition of human histone deacetylase 8 is dependent on the identity of the active site metal ion. Biochemistry 45(19):6170–6178

    CAS  Google Scholar 

  34. Bressi JC et al (2010) Exploration of the HDAC2 foot pocket: synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg Med Chem Lett 20(10):3142–3145

    CAS  Google Scholar 

  35. Somoza JR et al (2004) Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12(7):1325–1334

    CAS  Google Scholar 

  36. Vannini A et al (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc Natl Acad Sci USA 101(42):15064–15069

    CAS  Google Scholar 

  37. Bottomley MJ et al (2008) Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain. J Biol Chem 283(39):26694–26704

    CAS  Google Scholar 

  38. Schuetz A et al (2008) Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity. J Biol Chem 283(17):11355–11363

    CAS  Google Scholar 

  39. Finnin MS et al (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401(6749):188–193

    CAS  Google Scholar 

  40. Nielsen TK et al (2005) Crystal structure of a bacterial class 2 histone deacetylase homologue. J Mol Biol 354(1):107–120

    CAS  Google Scholar 

  41. Nielsen TK et al (2007) Complex structure of a bacterial class 2 histone deacetylase homologue with a trifluoromethylketone inhibitor. Acta Crystallogr F Struct Biol Cryst Commun 63(Pt 4):270–273

    Google Scholar 

  42. Guo L et al (2007) Crystal structure of a conserved N-terminal domain of histone deacetylase 4 reveals functional insights into glutamine-rich domains. Proc Natl Acad Sci USA 104(11):4297–4302

    CAS  Google Scholar 

  43. Itoh Y, Suzuki T, Miyata N (2008) Isoform-selective histone deacetylase inhibitors. Curr Pharm Des 14(6):529–544

    CAS  Google Scholar 

  44. Hitchcock SA, Pennington LD (2006) Structure-brain exposure relationships. J Med Chem 49(26):7559–7583

    CAS  Google Scholar 

  45. Klon AE (2009) Computational models for central nervous system penetration. Curr Comput Aided Drug Des 5(2):71–89

    CAS  Google Scholar 

  46. Carvey PM, Hendey B, Monahan AJ (2009) The blood-brain barrier in neurodegenerative disease: a rhetorical perspective. J Neurochem 111(2):291–314

    CAS  Google Scholar 

  47. Wang H, Dymock BW (2009) New patented histone deacetylase inhibitors. Expert Opin Ther Pat 19(12):1727–1757

    CAS  Google Scholar 

  48. Grozinger CM, Schreiber SL (2002) Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem Biol 9(1):3–16

    CAS  Google Scholar 

  49. Musso DL et al (2001) N-hydroxyformamide peptidomimetics as TACE/matrix metalloprotease inhibitors: oral activity via P1’ isobutyl substitution. Bioorg Med Chem Lett 11(16):2147–2151

    CAS  Google Scholar 

  50. Kattar SD et al (2009) Parallel medicinal chemistry approaches to selective HDAC1/HDAC2 inhibitor (SHI-1:2) optimization. Bioorg Med Chem Lett 19(4):1168–1172

    CAS  Google Scholar 

  51. Mai A et al (2005) Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides. J Med Chem 48(9):3344–3353

    CAS  Google Scholar 

  52. Cai X et al (2010) Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanam ide (CUDc-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J Med Chem 53(5):2000–2009

    CAS  Google Scholar 

  53. Hamblett CL et al (2007) The discovery of 6-amino nicotinamides as potent and selective histone deacetylase inhibitors. Bioorg Med Chem Lett 17(19):5300–5309

    CAS  Google Scholar 

  54. Suzuki T et al (1999) Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem 42(15):3001–3003

    CAS  Google Scholar 

  55. Ryan QC et al (2005) Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 23(17):3912–3922

    CAS  Google Scholar 

  56. Chou CJ, Herman D, Gottesfeld JM (2008) Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. J Biol Chem 283(51):35402–35409

    CAS  Google Scholar 

  57. Xu C et al (2009) Chemical probes identify a role for histone deacetylase 3 in Friedreich’s ataxia gene silencing. Chem Biol 16(9):980–989

    CAS  Google Scholar 

  58. Ueda H et al (1994) FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. J Antibiot (Tokyo) 47(3):301–310

    CAS  Google Scholar 

  59. Campas-Moya C (2009) Romidepsin for the treatment of cutaneous T-cell lymphoma. Drugs Today (Barc) 45(11):787–795

    Google Scholar 

  60. Taori K, Paul VJ, Luesch H (2008) Structure and activity of largazole, a potent antiproliferative agent from the Floridian marine cyanobacterium Symploca sp. J Am Chem Soc 130(6):1806–1807

    CAS  Google Scholar 

  61. Walton JD (2006) HC-toxin. Phytochemistry 67(14):1406–1413

    CAS  Google Scholar 

  62. Shute RE, Dunlap B, Rich DH (1987) Analogues of the cytostatic and antimitogenic agents chlamydocin and HC-toxin: synthesis and biological activity of chloromethyl ketone and diazomethyl ketone functionalized cyclic tetrapeptides. J Med Chem 30(1):71–78

    CAS  Google Scholar 

  63. Darkin-Rattray SJ et al (1996) Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA 93(23):13143–13147

    CAS  Google Scholar 

  64. Mori H et al (2003) FR235222, a fungal metabolite, is a novel immunosuppressant that inhibits mammalian histone deacetylase (HDAC). I. Taxonomy, fermentation, isolation and biological activities. J Antibiot (Tokyo) 56(2):72–79

    CAS  Google Scholar 

  65. Brasnjevic I et al (2009) Delivery of peptide and protein drugs over the blood-brain barrier. Prog Neurobiol 87(4):212–251

    CAS  Google Scholar 

  66. Montero A et al (2009) Design, synthesis, biological evaluation, and structural characterization of potent histone deacetylase inhibitors based on cyclic alpha/beta-tetrapeptide architectures. J Am Chem Soc 131(8):3033–3041

    CAS  Google Scholar 

  67. Olsen CA, Ghadiri MR (2009) Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic α3β-tetrapeptides. J Med Chem 52(23):7836–7846

    CAS  Google Scholar 

  68. Jones P et al (2006) A series of novel, potent, and selective histone deacetylase inhibitors. Bioorg Med Chem Lett 16(23):5948–5952

    CAS  Google Scholar 

  69. Jones P et al (2008) A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo. J Med Chem 51(8):2350–2353

    CAS  Google Scholar 

  70. Kinzel O et al (2009) Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties. J Med Chem 52(11):3453–3456

    CAS  Google Scholar 

  71. Frey RR et al (2002) Trifluoromethyl ketones as inhibitors of histone deacetylase. Bioorg Med Chem Lett 12(23):3443–3447

    CAS  Google Scholar 

  72. Muraglia E et al (2008) 2-Trifluoroacetylthiophene oxadiazoles as potent and selective class II human histone deacetylase inhibitors. Bioorg Med Chem Lett 18(23):6083–6087

    CAS  Google Scholar 

  73. Scarpelli R et al (2008) Studies of the metabolic stability in cells of 5-(trifluoroacetyl)thiophene-2-carboxamides and identification of more stable class II histone deacetylase (HDAC) inhibitors. Bioorg Med Chem Lett 18(23):6078–6082

    CAS  Google Scholar 

  74. Ontoria JM et al (2009) Identification of novel, selective, and stable inhibitors of class II histone deacetylases. Validation studies of the inhibition of the enzymatic activity of HDAC4 by small molecules as a novel approach for cancer therapy. J Med Chem 52(21):6782–6789

    CAS  Google Scholar 

  75. Chen JS, Faller DV, Spanjaard RA (2003) Short-chain fatty acid inhibitors of histone deacetylases: promising anticancer therapeutics? Curr Cancer Drug Targets 3(3):219–236

    CAS  Google Scholar 

  76. Riggs MG et al (1977) n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268(5619):462–464

    CAS  Google Scholar 

  77. Blank-Porat D et al (2007) The anticancer prodrugs of butyric acid AN-7 and AN-9, possess antiangiogenic properties. Cancer Lett 256(1):39–48

    CAS  Google Scholar 

  78. Kothari V et al (2010) HDAC inhibitor valproic acid enhances tumor cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model. Int J Cancer 126(3):733–742

    CAS  Google Scholar 

  79. Ryningen A, Stapnes C, Bruserud O (2007) Clonogenic acute myelogenous leukemia cells are heterogeneous with regard to regulation of differentiation and effect of epigenetic pharmacological targeting. Leuk Res 31(9):1303–1313

    CAS  Google Scholar 

  80. Yang PM et al (2010) Inhibition of histone deacetylase activity is a novel function of the antifolate drug methotrexate. Biochem Biophys Res Commun 391(3):1396–1399

    CAS  Google Scholar 

  81. Bradner JE et al (2010) Chemical phylogenetics of histone deacetylases. Nat Chem Biol 6(3):238–243

    CAS  Google Scholar 

  82. Riester D et al (2004) Members of the histone deacetylase superfamily differ in substrate specificity towards small synthetic substrates. Biochem Biophys Res Commun 324(3):1116–1123

    CAS  Google Scholar 

  83. Su H, Altucci L, You Q (2008) Competitive or noncompetitive, that’s the question: research toward histone deacetylase inhibitors. Mol Cancer Ther 7(5):1007–1012

    CAS  Google Scholar 

  84. Anastasiou D, Krek W (2006) SIRT1: linking adaptive cellular responses to aging-associated changes in organismal physiology. Physiology (Bethesda) 21:404–410

    CAS  Google Scholar 

  85. North BJ, Verdin E (2007) Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS ONE 2(8):e784

    Google Scholar 

  86. Werner HB et al (2007) Proteolipid protein is required for transport of sirtuin 2 into CNS myelin. J Neurosci 27(29):7717–7730

    CAS  Google Scholar 

  87. Li W et al (2007) Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating alpha-tubulin. J Neurosci 27(10):2606–2616

    Google Scholar 

  88. Ahuja N et al (2007) Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem 282(46):33583–33592

    CAS  Google Scholar 

  89. Jin D et al (2009) Molecular cloning and characterization of porcine sirtuin genes. Comp Biochem Physiol B Biochem Mol Biol 153(4):348–358

    CAS  Google Scholar 

  90. Michishita E et al (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16(10):4623–4635

    CAS  Google Scholar 

  91. Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289(5487):2126–2128

    CAS  Google Scholar 

  92. Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA 101(45):15998–16003

    CAS  Google Scholar 

  93. Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410(6825):227–230

    CAS  Google Scholar 

  94. Cohen HY et al (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305(5682):390–392

    CAS  Google Scholar 

  95. Tang BL, Chua CE (2008) SIRT1 and neuronal diseases. Mol Aspects Med 29(3):187–200

    CAS  Google Scholar 

  96. Luo J et al (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107(2):137–148

    CAS  Google Scholar 

  97. Smith BC, Denu JM (2006) Sirtuins caught in the act. Structure 14(8):1207–1208

    CAS  Google Scholar 

  98. Finnin MS, Donigian JR, Pavletich NP (2001) Structure of the histone deacetylase SIRT2. Nat Struct Biol 8(7):621–625

    CAS  Google Scholar 

  99. Min J et al (2001) Crystal structure of a SIR2 homolog-NAD complex. Cell 105(2):269–279

    CAS  Google Scholar 

  100. Chang JH et al (2002) Structural basis for the NAD-dependent deacetylase mechanism of Sir2. J Biol Chem 277(37):34489–34498

    CAS  Google Scholar 

  101. Avalos JL et al (2002) Structure of a Sir2 enzyme bound to an acetylated p53 peptide. Mol Cell 10(3):523–535

    CAS  Google Scholar 

  102. Zhao K et al (2003) Structure and autoregulation of the yeast Hst2 homolog of Sir2. Nat Struct Biol 10(10):864–871

    CAS  Google Scholar 

  103. Zhao K, Chai X, Marmorstein R (2003) Structure of the yeast Hst2 protein deacetylase in ternary complex with 2’-O-acetyl ADP ribose and histone peptide. Structure 11(11):1403–1411

    CAS  Google Scholar 

  104. Zhao K, Chai X, Marmorstein R (2004) Structure and substrate binding properties of cobB, a Sir2 homolog protein deacetylase from Escherichia coli. J Mol Biol 337(3):731–741

    CAS  Google Scholar 

  105. Zhao K et al (2004) Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases. Proc Natl Acad Sci USA 101(23):8563–8568

    CAS  Google Scholar 

  106. Avalos JL, Bever KM, Wolberger C (2005) Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell 17(6):855–868

    CAS  Google Scholar 

  107. Avalos JL, Boeke JD, Wolberger C (2004) Structural basis for the mechanism and regulation of Sir2 enzymes. Mol Cell 13(5):639–648

    CAS  Google Scholar 

  108. Cosgrove MS et al (2006) The structural basis of sirtuin substrate affinity. Biochemistry 45(24):7511–7521

    CAS  Google Scholar 

  109. Hoff KG et al (2006) Insights into the sirtuin mechanism from ternary complexes containing NAD+ and acetylated peptide. Structure 14(8):1231–1240

    CAS  Google Scholar 

  110. Schuetz A et al (2007) Structural basis of inhibition of the human NAD+ -dependent deacetylase SIRT5 by suramin. Structure 15(3):377–389

    CAS  Google Scholar 

  111. Sauve AA et al (2001) Chemistry of gene silencing: the mechanism of NAD+ -dependent deacetylation reactions. Biochemistry 40(51):15456–15463

    CAS  Google Scholar 

  112. Hawse WF et al (2008) Structural insights into intermediate steps in the Sir2 deacetylation reaction. Structure 16(9):1368–1377

    CAS  Google Scholar 

  113. Smith BC, Denu JM (2006) Sir2 protein deacetylases: evidence for chemical intermediates and functions of a conserved histidine. Biochemistry 45(1):272–282

    CAS  Google Scholar 

  114. Sauve AA et al (2006) The biochemistry of sirtuins. Annu Rev Biochem 75:435–465

    CAS  Google Scholar 

  115. Yamamoto H, Schoonjans K, Auwerx J (2007) Sirtuin functions in health and disease. Mol Endocrinol 21(8):1745–1755

    CAS  Google Scholar 

  116. Grozinger CM et al (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 276(42):38837–38843

    CAS  Google Scholar 

  117. Heltweg B et al (2006) Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res 66(8):4368–4377

    CAS  Google Scholar 

  118. Lain S et al (2008) Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13(5):454–463

    CAS  Google Scholar 

  119. Tervo AJ et al (2006) Discovering inhibitors of human sirtuin type 2: novel structural scaffolds. J Med Chem 49(24):7239–7241

    CAS  Google Scholar 

  120. Sanders BD et al (2009) Identification and characterization of novel sirtuin inhibitor scaffolds. Bioorg Med Chem 17(19):7031–7041

    CAS  Google Scholar 

  121. Huber K et al (2010) Novel 3-arylideneindolin-2-ones as inhibitors of NAD + -dependent histone deacetylases (sirtuins). J Med Chem 53(3):1383–1386

    CAS  Google Scholar 

  122. Napper AD et al (2005) Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem 48(25):8045–8054

    CAS  Google Scholar 

  123. Pallos J et al (2008) Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum Mol Genet 17(23):3767–3775

    CAS  Google Scholar 

  124. Ghosh S, Feany MB (2004) Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases. Hum Mol Genet 13(18):2011–2018

    CAS  Google Scholar 

  125. Parker JA et al (2005) Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 37(4):349–350

    CAS  Google Scholar 

  126. Kumar P et al (2006) Effect of resveratrol on 3-nitropropionic acid-induced biochemical and behavioural changes: possible neuroprotective mechanisms. Behav Pharmacol 17(5–6):485–492

    CAS  Google Scholar 

  127. Milne JC et al (2007) Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450(7170):712–716

    CAS  Google Scholar 

  128. Vu CB et al (2009) Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators. J Med Chem 52(5):1275–1283

    Google Scholar 

  129. Pacholec M et al (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285(11):8340–8351

    CAS  Google Scholar 

  130. Bemis JE et al (2009) Discovery of oxazolo[4, 5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators. Bioorg Med Chem Lett 19(8):2350–2353

    CAS  Google Scholar 

  131. Nayagam VM et al (2006) SIRT1 modulating compounds from high-throughput screening as anti-inflammatory and insulin-sensitizing agents. J Biomol Screen 11(8):959–967

    CAS  Google Scholar 

  132. Mai A et al (2009) Study of 1, 4-dihydropyridine structural scaffold: discovery of novel sirtuin activators and inhibitors. J Med Chem 52(17):5496–5504

    CAS  Google Scholar 

  133. Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447(7143):407–412

    CAS  Google Scholar 

  134. Horn PJ, Peterson CL (2002) Molecular biology. Chromatin higher order folding – wrapping up transcription. Science 297(5588):1824–1827

    CAS  Google Scholar 

  135. Keppler BR, Archer TK (2008) Chromatin-modifying enzymes as therapeutic targets–Part 1. Expert Opin Ther Targets 12(10):1301–1312

    CAS  Google Scholar 

  136. Colangelo V et al (2002) Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 70(3):462–473

    CAS  Google Scholar 

  137. Kitamura Y et al (1997) Alteration of transcription factors NF-κB and STAT1 in Alzheimer’s disease brains. Neurosci Lett 237(1):17–20

    CAS  Google Scholar 

  138. Bossers K et al (2009) Analysis of gene expression in Parkinson’s disease: possible involvement of neurotrophic support and axon guidance in dopaminergic cell death. Brain Pathol 19(1):91–107

    CAS  Google Scholar 

  139. Sutherland GT et al (2009) A cross-study transcriptional analysis of Parkinson’s disease. PLoS ONE 4(3):e4955

    Google Scholar 

  140. Mandel S et al (2005) Gene expression profiling of sporadic Parkinson’s disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. Ann NY Acad Sci 1053:356–375

    CAS  Google Scholar 

  141. Vogt IR et al (2006) Transcriptional changes in multiple system atrophy and Parkinson’s disease putamen. Exp Neurol 199(2):465–478

    CAS  Google Scholar 

  142. Iivonen S et al (2002) Seladin-1 transcription is linked to neuronal degeneration in Alzheimer’s disease. Neuroscience 113(2):301–310

    CAS  Google Scholar 

  143. Yacoubian TA et al (2008) Transcriptional dysregulation in a transgenic model of Parkinson disease. Neurobiol Dis 29(3):515–528

    CAS  Google Scholar 

  144. Robakis NK (2003) An Alzheimer’s disease hypothesis based on transcriptional dysregulation. Amyloid 10(2):80–85

    CAS  Google Scholar 

  145. Hodges A et al (2006) Regional and cellular gene expression changes in human Huntington’s disease brain. Hum Mol Genet 15(6):965–977

    CAS  Google Scholar 

  146. Strand AD et al (2005) Gene expression in Huntington’s disease skeletal muscle: a potential biomarker. Hum Mol Genet 14(13):1863–1876

    CAS  Google Scholar 

  147. Becanovic K et al (2010) Transcriptional changes in Huntington disease identified using genome-wide expression profiling and cross-platform analysis. Hum Mol Genet 19(8):1438–1452

    Google Scholar 

  148. Mazarei G et al (2010) Expression analysis of novel striatal-enriched genes in Huntington disease. Hum Mol Genet 19(4):609–622

    CAS  Google Scholar 

  149. Kuhn A et al (2007) Mutant huntingtin’s effects on striatal gene expression in mice recapitulate changes observed in human Huntington’s disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum Mol Genet 16(15):1845–1861

    CAS  Google Scholar 

  150. Luthi-Carter R et al (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9(9):1259–1271

    CAS  Google Scholar 

  151. Chiang MC et al (2007) Systematic uncovering of multiple pathways underlying the pathology of Huntington disease by an acid-cleavable isotope-coded affinity tag approach. Mol Cell Proteomics 6(5):781–797

    CAS  Google Scholar 

  152. Luthi-Carter R et al (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington’s disease mouse models reveal context-independent effects. Hum Mol Genet 11(17):1927–1937

    CAS  Google Scholar 

  153. Huen NY, Wong SL, Chan HY (2007) Transcriptional malfunctioning of heat shock protein gene expression in spinocerebellar ataxias. Cerebellum 6(2):111–117

    CAS  Google Scholar 

  154. Fuchs J et al (2009) The transcription factor PITX3 is associated with sporadic Parkinson’s disease. Neurobiol Aging 30(5):731–738

    CAS  Google Scholar 

  155. Le W et al (2009) Transcription factor PITX3 gene in Parkinson’s disease. Neurobiol Aging [Epub ahead of print]

    Google Scholar 

  156. Li J, Dani JA, Le W (2009) The role of transcription factor Pitx3 in dopamine neuron development and Parkinson’s disease. Curr Top Med Chem 9(10):855–859

    CAS  Google Scholar 

  157. Jacobsen KX et al (2008) A Nurr1 point mutant, implicated in Parkinson’s disease, uncouples ERK1/2-dependent regulation of tyrosine hydroxylase transcription. Neurobiol Dis 29(1):117–122

    CAS  Google Scholar 

  158. Xu J et al (2005) The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum Mol Genet 14(9):1231–1241

    CAS  Google Scholar 

  159. da Costa CA, Checler F (2010) A novel parkin-mediated transcriptional function links p53 to familial Parkinson’s disease. Cell Cycle 9(1):16–17

    Google Scholar 

  160. Jeong SJ et al (2005) Activated AKT regulates NF-kappaB activation, p53 inhibition and cell survival in HTLV-1-transformed cells. Oncogene 24(44):6719–6728

    CAS  Google Scholar 

  161. da Costa CA et al (2009) Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson’s disease. Nat Cell Biol 11(11):1370–1375

    Google Scholar 

  162. Ryan AB, Zeitlin SO, Scrable H (2006) Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington’s disease pathogenesis. Neurobiol Dis 24(2):419–427

    CAS  Google Scholar 

  163. Seong IS et al (2010) Huntingtin facilitates polycomb repressive complex 2. Hum Mol Genet 19(4):573–583

    CAS  Google Scholar 

  164. Hughes RE (2002) Polyglutamine disease: acetyltransferases awry. Curr Biol 12(4):R141–R143

    CAS  Google Scholar 

  165. McCampbell A, Fischbeck KH (2001) Polyglutamine and CBP: fatal attraction? Nat Med 7(5):528–530

    CAS  Google Scholar 

  166. Kwok RP et al (1994) Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370(6486):223–226

    CAS  Google Scholar 

  167. Janknecht R (2002) The versatile functions of the transcriptional coactivators p300 and CBP and their roles in disease. Histol Histopathol 17(2):657–668

    CAS  Google Scholar 

  168. McManus KJ, Hendzel MJ (2001) CBP, a transcriptional coactivator and acetyltransferase. Biochem Cell Biol 79(3):253–266

    CAS  Google Scholar 

  169. Rouaux C, Loeffler JP, Boutillier AL (2004) Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders. Biochem Pharmacol 68(6):1157–1164

    CAS  Google Scholar 

  170. Lin CH et al (2001) A small domain of CBP/p300 binds diverse proteins: solution structure and functional studies. Mol Cell 8(3):581–590

    CAS  Google Scholar 

  171. Perutz MF et al (2002) Aggregation of proteins with expanded glutamine and alanine repeats of the glutamine-rich and asparagine-rich domains of Sup35 and of the amyloid beta-peptide of amyloid plaques. Proc Natl Acad Sci USA 99(8):5596–5600

    CAS  Google Scholar 

  172. Fu L, Gao YS, Sztul E (2005) Transcriptional repression and cell death induced by nuclear aggregates of non-polyglutamine protein. Neurobiol Dis 20(3):656–665

    CAS  Google Scholar 

  173. McCampbell A et al (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9(14):2197–2202

    CAS  Google Scholar 

  174. Nucifora FC Jr et al (2001) Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291(5512):2423–2428

    CAS  Google Scholar 

  175. Jiang H et al (2006) Depletion of CBP is directly linked with cellular toxicity caused by mutant huntingtin. Neurobiol Dis 23(3):543–551

    CAS  Google Scholar 

  176. Li F et al (2002) Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem 277(47):45004–45012

    CAS  Google Scholar 

  177. Steffan JS et al (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413(6857):739–743

    CAS  Google Scholar 

  178. Barrett RM, Wood MA (2008) Beyond transcription factors: the role of chromatin modifying enzymes in regulating transcription required for memory. Learn Mem 15(7):460–467

    CAS  Google Scholar 

  179. Hardy S et al (2002) TATA-binding protein-free TAF-containing complex (TFTC) and p300 are both required for efficient transcriptional activation. J Biol Chem 277(36):32875–32882

    CAS  Google Scholar 

  180. Helmlinger D et al (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 13(12):1257–1265

    CAS  Google Scholar 

  181. Friedman MJ et al (2008) Polyglutamine expansion reduces the association of TATA-binding protein with DNA and induces DNA binding-independent neurotoxicity. J Biol Chem 283(13):8283–8290

    CAS  Google Scholar 

  182. Friedman MJ et al (2007) Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration. Nat Neurosci 10(12):1519–1528

    CAS  Google Scholar 

  183. Schaffar G et al (2004) Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol Cell 15(1):95–105

    CAS  Google Scholar 

  184. Palhan VB et al (2005) Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci USA 102(24):8472–8477

    CAS  Google Scholar 

  185. Helmlinger D et al (2006) Both normal and polyglutamine- expanded ataxin-7 are components of TFTC-type GCN5 histone acetyltransferase-containing complexes. Biochem Soc Symp 73:155–163

    CAS  Google Scholar 

  186. Malaspina A, Kaushik N, de Belleroche J (2001) Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. J Neurochem 77(1):132–145

    CAS  Google Scholar 

  187. Ishigaki S et al (2002) Differentially expressed genes in sporadic amyotrophic lateral sclerosis spinal cords–screening by molecular indexing and subsequent cDNA microarray analysis. FEBS Lett 531(2):354–358

    CAS  Google Scholar 

  188. Yoshihara T et al (2002) Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 80(1):158–167

    CAS  Google Scholar 

  189. McCampbell A et al (2001) Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci USA 98(26):15179–15184

    CAS  Google Scholar 

  190. Sadri-Vakili G et al (2007) Histones associated with downregulated genes are hypo-acetylated in Huntington’s disease models. Hum Mol Genet 16(11):1293–1306

    CAS  Google Scholar 

  191. Bates EA et al (2006) Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity. J Neurosci 26(10):2830–2838

    CAS  Google Scholar 

  192. Taylor JP et al (2003) Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev 17(12):1463–1468

    CAS  Google Scholar 

  193. Ferrante RJ et al (2003) Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci 23(28):9418–9427

    CAS  Google Scholar 

  194. Van Lint C, Emiliani S, Verdin E (1996) The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr 5(4–5):245–253

    Google Scholar 

  195. Gray SG et al (2004) Microarray profiling of the effects of histone deacetylase inhibitors on gene expression in cancer cell lines. Int J Oncol 24(4):773–795

    CAS  Google Scholar 

  196. Smith CL (2008) A shifting paradigm: histone deacetylases and transcriptional activation. Bioessays 30(1):15–24

    CAS  Google Scholar 

  197. Ying M et al (2006) Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA. J Biol Chem 281(18):12580–12586

    CAS  Google Scholar 

  198. Ryu H et al (2005) Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. J Neurochem 93(5):1087–1098

    CAS  Google Scholar 

  199. Marmolino D, Acquaviva F (2009) Friedreich’s Ataxia: from the (GAA)n repeat mediated silencing to new promising molecules for therapy. Cerebellum 8(3):245–259

    CAS  Google Scholar 

  200. Herman D et al (2006) Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat Chem Biol 2(10):551–558

    CAS  Google Scholar 

  201. Rai M et al (2008) HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS ONE 3(4):e1958

    Google Scholar 

  202. Thomas EA et al (2008) The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington’s disease transgenic mice. Proc Natl Acad Sci USA 105(40):15564–15569

    CAS  Google Scholar 

  203. Hockly E et al (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci USA 100(4):2041–2046

    CAS  Google Scholar 

  204. Tank EM, True HL (2009) Disease-associated mutant ubiquitin causes proteasomal impairment and enhances the toxicity of protein aggregates. PLoS Genet 5(2):e1000382

    Google Scholar 

  205. Hol EM, van Leeuwen FW, Fischer DF (2005) The proteasome in Alzheimer’s disease and Parkinson’s disease: lessons from ubiquitin B + 1. Trends Mol Med 11(11):488–495

    CAS  Google Scholar 

  206. Staropoli JF et al (2003) Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 37(5):735–749

    CAS  Google Scholar 

  207. Lehman NL (2009) The ubiquitin proteasome system in neuropathology. Acta Neuropathol 118(3):329–347

    CAS  Google Scholar 

  208. Spange S et al (2009) Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol 41(1):185–198

    CAS  Google Scholar 

  209. Sadoul K et al (2008) Regulation of protein turnover by acetyltransferases and deacetylases. Biochimie 90(2):306–312

    CAS  Google Scholar 

  210. Scroggins BT et al (2007) An acetylation site in the middle domain of Hsp90 regulates chaperone function. Mol Cell 25(1):151–159

    CAS  Google Scholar 

  211. Jeong H et al (2009) Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137(1):60–72

    CAS  Google Scholar 

  212. Caron C, Boyault C, Khochbin S (2005) Regulatory cross-talk between lysine acetylation and ubiquitination: role in the control of protein stability. Bioessays 27(4):408–415

    CAS  Google Scholar 

  213. Ito A et al (2002) MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation. EMBO J 21(22):6236–6245

    CAS  Google Scholar 

  214. Mookerjee S et al (2009) Posttranslational modification of ataxin-7 at lysine 257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment. J Neurosci 29(48):15134–15144

    CAS  Google Scholar 

  215. Grossman SR et al (2003) Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 300(5617):342–344

    CAS  Google Scholar 

  216. Kass EM et al (2009) Mdm2 and PCAF increase Chk2 ubiquitination and degradation independently of their intrinsic E3 ligase activities. Cell Cycle 8(3):430–437

    CAS  Google Scholar 

  217. Linares LK et al (2007) Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2. Nat Cell Biol 9(3):331–338

    CAS  Google Scholar 

  218. Seigneurin-Berny D et al (2001) Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol Cell Biol 21(23):8035–8044

    CAS  Google Scholar 

  219. Hook SS et al (2002) Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Proc Natl Acad Sci USA 99(21):13425–13430

    CAS  Google Scholar 

  220. Kirsh O et al (2002) The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J 21(11):2682–2691

    CAS  Google Scholar 

  221. Takahashi-Fujigasaki J, Fujigasaki H (2006) Histone deacetylase (HDAC) 4 involvement in both Lewy and Marinesco bodies. Neuropathol Appl Neurobiol 32(5):562–566

    CAS  Google Scholar 

  222. Steffan JS et al (2004) SUMO modification of Huntingtin and Huntington’s disease pathology. Science 304(5667):100–104

    CAS  Google Scholar 

  223. Terashima T et al (2002) SUMO-1 co-localized with mutant atrophin-1 with expanded polyglutamines accelerates intranuclear aggregation and cell death. NeuroReport 13(17):2359–2364

    CAS  Google Scholar 

  224. Riley BE, Zoghbi HY, Orr HT (2005) SUMOylation of the polyglutamine repeat protein, ataxin-1, is dependent on a functional nuclear localization signal. J Biol Chem 280(23):21942–21948

    CAS  Google Scholar 

  225. Pandey UB et al (2007) HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration. Autophagy 3(6):643–645

    CAS  Google Scholar 

  226. Pandey UB et al (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447(7146):859–863

    CAS  Google Scholar 

  227. Simms-Waldrip T et al (2008) The aggresome pathway as a target for therapy in hematologic malignancies. Mol Genet Metab 94(3):283–286

    CAS  Google Scholar 

  228. Kawaguchi Y et al (2003) The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115(6):727–738

    CAS  Google Scholar 

  229. Kopito RR (2003) The missing linker: an unexpected role for a histone deacetylase. Mol Cell 12(6):1349–1351

    CAS  Google Scholar 

  230. Iwata A et al (2005) HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J Biol Chem 280(48):40282–40292

    CAS  Google Scholar 

  231. Perez M et al (2009) Tau – an inhibitor of deacetylase HDAC6 function. J Neurochem 109(6):1756–1766

    CAS  Google Scholar 

  232. Matthias P, Yoshida M, Khochbin S (2008) HDAC6 a new cellular stress surveillance factor. Cell Cycle 7(1):7–10

    CAS  Google Scholar 

  233. Reed NA et al (2006) Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16(21):2166–2172

    CAS  Google Scholar 

  234. Gauthier LR et al (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118(1):127–138

    CAS  Google Scholar 

  235. Dompierre JP et al (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci 27(13):3571–3583

    CAS  Google Scholar 

  236. Rivieccio MA et al (2009) HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci USA 106(46):19599–19604

    CAS  Google Scholar 

  237. Itoh Y et al (2007) Design, synthesis, structure–selectivity relationship, and effect on human cancer cells of a novel series of histone deacetylase 6-selective inhibitors. J Med Chem 50(22):5425–5438

    CAS  Google Scholar 

  238. Haggarty SJ et al (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA 100(8):4389–4394

    CAS  Google Scholar 

  239. Schafer S et al (2008) Phenylalanine-containing hydroxamic acids as selective inhibitors of class IIb histone deacetylases (HDACs). Bioorg Med Chem 16(4):2011–2033

    Google Scholar 

  240. Schafer S et al (2009) Pyridylalanine-containing hydroxamic acids as selective HDAC6 inhibitors. ChemMedChem 4(2):283–290

    Google Scholar 

  241. Kozikowski AP et al (2008) Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: a new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6. J Med Chem 51(15):4370–4373

    CAS  Google Scholar 

  242. Smil DV et al (2009) Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors. Bioorg Med Chem Lett 19(3):688–692

    CAS  Google Scholar 

  243. Oh M, Choi IK, Kwon HJ (2008) Inhibition of histone deacetylase1 induces autophagy. Biochem Biophys Res Commun 369(4):1179–1183

    CAS  Google Scholar 

  244. Lee IH et al (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105(9):3374–3379

    CAS  Google Scholar 

  245. Jeong MR et al (2003) Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition. FEBS Lett 542(1–3):74–78

    CAS  Google Scholar 

  246. Langley B et al (2008) Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21(waf1/cip1) in cell cycle-independent neuroprotection. J Neurosci 28(1):163–176

    CAS  Google Scholar 

  247. Ryu H et al (2003) Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci USA 100(7):4281–4286

    CAS  Google Scholar 

  248. Uo T, Veenstra TD, Morrison RS (2009) Histone deacetylase inhibitors prevent p53-dependent and p53-independent Bax-mediated neuronal apoptosis through two distinct mechanisms. J Neurosci 29(9):2824–2832

    CAS  Google Scholar 

  249. Leng Y, Chuang DM (2006) Endogenous alpha-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. J Neurosci 26(28):7502–7512

    CAS  Google Scholar 

  250. 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(12):1116–1125

    CAS  Google Scholar 

  251. Peng GS et al (2005) Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Res Mol Brain Res 134(1):162–169

    CAS  Google Scholar 

  252. Chen PS et al (2007) Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 149(1):203–212

    CAS  Google Scholar 

  253. Yasuda S et al (2009) The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry 14(1):51–59

    CAS  Google Scholar 

  254. Wu X et al (2008) Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol 11(8):1123–1134

    CAS  Google Scholar 

  255. Kim HJ, Leeds P, Chuang DM (2009) The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J Neurochem 110(4):1226–1240

    CAS  Google Scholar 

  256. Adcock IM (2007) HDAC inhibitors as anti-inflammatory agents. Br J Pharmacol 150(7): 829–831

    CAS  Google Scholar 

  257. Glauben R et al (2009) HDAC inhibitors in models of inflammation-related tumorigenesis. Cancer Lett 280(2):154–159

    CAS  Google Scholar 

  258. Halili MA et al (2009) Histone deacetylase inhibitors in inflammatory disease. Curr Top Med Chem 9(3):309–319

    CAS  Google Scholar 

  259. Zhang B et al (2008) HDAC inhibitor increases histone H3 acetylation and reduces microglia inflammatory response following traumatic brain injury in rats. Brain Res 1226:181–191

    CAS  Google Scholar 

  260. Dinarello CA (2006) Inhibitors of histone deacetylases as anti-inflammatory drugs. Ernst Schering Res Found Workshop 56:45–60

    Google Scholar 

  261. Ren M et al (2004) Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem 89(6):1358–1367

    CAS  Google Scholar 

  262. Faraco G et al (2006) Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol Pharmacol 70(6):1876–1884

    CAS  Google Scholar 

  263. Camelo S et al (2005) Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol 164(1–2):10–21

    CAS  Google Scholar 

  264. Granger A et al (2008) Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J 22(10):3549–3560

    CAS  Google Scholar 

  265. Bolger TA, Yao TP (2005) Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death. J Neurosci 25(41):9544–9553

    CAS  Google Scholar 

  266. Linseman DA et al (2003) Inactivation of the myocyte enhancer factor-2 repressor histone deacetylase-5 by endogenous Ca2+ calmodulin-dependent kinase II promotes depolarization-mediated cerebellar granule neuron survival. J Biol Chem 278(42):41472–41481

    CAS  Google Scholar 

  267. Majdzadeh N et al (2008) HDAC4 inhibits cell-cycle progression and protects neurons from cell death. Dev Neurobiol 68(8):1076–1092

    CAS  Google Scholar 

  268. Chen B, Cepko CL (2009) HDAC4 regulates neuronal survival in normal and diseased retinas. Science 323(5911):256–259

    CAS  Google Scholar 

  269. Outeiro TF, Marques O, Kazantsev A (2008) Therapeutic role of sirtuins in neurodegenerative disease. Biochim Biophys Acta 1782(6):363–369

    CAS  Google Scholar 

  270. Westphal CH, Dipp MA, Guarente L (2007) A therapeutic role for sirtuins in diseases of aging? Trends Biochem Sci 32(12):555–560

    CAS  Google Scholar 

  271. Kim D et al (2007) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 26(13):3169–3179

    CAS  Google Scholar 

  272. Li Y et al (2007) Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation. Cell Death Differ 14(12):2058–2067

    CAS  Google Scholar 

  273. Houten SM, Auwerx J (2004) PGC-1alpha: turbocharging mitochondria. Cell 119(1):5–7

    CAS  Google Scholar 

  274. Cui L et al (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127(1):59–69

    CAS  Google Scholar 

  275. Dominy JE Jr et al (2010) Nutrient-dependent regulation of PGC-1alpha’s acetylation state and metabolic function through the enzymatic activities of Sirt1/GCN5. Biochim Biophys Acta 1804(8):1676–1683

    CAS  Google Scholar 

  276. Rodgers JT et al (2008) Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 582(1):46–53

    CAS  Google Scholar 

  277. Rodgers JT et al (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434(7029):113–118

    CAS  Google Scholar 

  278. Sugden MC, Caton PW, Holness MJ (2010) PPAR control: it’s SIRTainly as easy as PGC. J Endocrinol 204(2):93–104

    CAS  Google Scholar 

  279. Garske AL, Smith BC, Denu JM (2007) Linking SIRT2 to Parkinson’s disease. ACS Chem Biol 2(8):529–532

    CAS  Google Scholar 

  280. Outeiro TF et al (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317(5837):516–519

    CAS  Google Scholar 

  281. Luthi-Carter R et al (2010) SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci USA 107(17):7927–7932

    CAS  Google Scholar 

  282. Pfister JA et al (2008) Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLoS ONE 3(12):e4090

    Google Scholar 

  283. Bonda DJ et al (2010) Mitochondrial dynamics in Alzheimer’s disease: opportunities for future treatment strategies. Drugs Aging 27(3):181–192

    CAS  Google Scholar 

  284. Burchell VS et al (2010) Targeting mitochondrial dysfunction in neurodegenerative disease: Part I. Expert Opin Ther Targets 14(4):369–385

    CAS  Google Scholar 

  285. Moreira PI et al (2010) Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta 1802(1):212–220

    CAS  Google Scholar 

  286. Su B et al (2010) Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim Biophys Acta 1802(1):135–142

    CAS  Google Scholar 

  287. Levenson JM et al (2004) Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279(39):40545–40559

    CAS  Google Scholar 

  288. Alarcon JM et al (2004) Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42(6):947–959

    CAS  Google Scholar 

  289. Bailey CH, Bartsch D, Kandel ER (1996) Toward a molecular definition of long-term memory storage. Proc Natl Acad Sci USA 93(24):13445–13452

    CAS  Google Scholar 

  290. Martin SJ, Grimwood PD, Morris RG (2000) Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23:649–711

    CAS  Google Scholar 

  291. Kandel ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294(5544):1030–1038

    CAS  Google Scholar 

  292. Maren S, Baudry M (1995) Properties and mechanisms of long-term synaptic plasticity in the mammalian brain: relationships to learning and memory. Neurobiol Learn Mem 63(1):1–18

    CAS  Google Scholar 

  293. Petersen RC et al (2009) Mild cognitive impairment: ten years later. Arch Neurol 66(12):1447–1455

    Google Scholar 

  294. Gabelle A et al (2010) Neurodegenerative dementia and parkinsonism. J Nutr Health Aging 14(1):37–44

    CAS  Google Scholar 

  295. Levy JA, Chelune GJ (2007) Cognitive-behavioral profiles of neurodegenerative dementias: beyond Alzheimer’s disease. J Geriatr Psychiatry Neurol 20(4):227–238

    Google Scholar 

  296. Bourne C et al (2006) Cognitive impairment and behavioural difficulties in patients with Huntington’s disease. Nurs Stand 20(35):41–44

    Google Scholar 

  297. Buccafusco JJ (2009) Emerging cognitive enhancing drugs. Expert Opin Emerg Drugs 14(4):577–589

    CAS  Google Scholar 

  298. Dash PK, Orsi SA, Moore AN (2009) Histone deactylase inhibition combined with behavioral therapy enhances learning and memory following traumatic brain injury. Neuroscience 163(1):1–8

    Google Scholar 

  299. Stefanko DP et al (2009) Modulation of long-term memory for object recognition via HDAC inhibition. Proc Natl Acad Sci USA 106(23):9447–9452

    CAS  Google Scholar 

  300. Bredy TW, Barad M (2008) The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Learn Mem 15(1):39–45

    CAS  Google Scholar 

  301. Bredy TW et al (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem 14(4):268–276

    CAS  Google Scholar 

  302. Vecsey CG et al (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci 27(23):6128–6140

    CAS  Google Scholar 

  303. Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42(6):961–972

    CAS  Google Scholar 

  304. Yeh SH, Lin CH, Gean PW (2004) Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory. Mol Pharmacol 65(5):1286–1292

    CAS  Google Scholar 

  305. Yamin G (2009) NMDA receptor-dependent signaling pathways that underlie amyloid beta-protein disruption of LTP in the hippocampus. J Neurosci Res 87(8):1729–1736

    CAS  Google Scholar 

  306. Viola KL, Velasco PT, Klein WL (2008) Why Alzheimer’s is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging 12(1):51S–57S

    CAS  Google Scholar 

  307. Rowan MJ et al (2007) Synaptic memory mechanisms: Alzheimer’s disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans 35(Pt 5):1219–1223

    CAS  Google Scholar 

  308. Rowan MJ et al (2003) Synaptic plasticity in animal models of early Alzheimer’s disease. Philos Trans R Soc Lond B Biol Sci 358(1432):821–828

    CAS  Google Scholar 

  309. Lynch G et al (2008) The substrates of memory: defects, treatments, and enhancement. Eur J Pharmacol 585(1):2–13

    CAS  Google Scholar 

  310. Di Filippo M et al (2007) Plastic abnormalities in experimental Huntington’s disease. Curr Opin Pharmacol 7(1):106–111

    Google Scholar 

  311. Smith R, Brundin P, Li JY (2005) Synaptic dysfunction in Huntington’s disease: a new perspective. Cell Mol Life Sci 62(17):1901–1912

    CAS  Google Scholar 

  312. Kung VW et al (2007) Dopamine-dependent long term potentiation in the dorsal striatum is reduced in the R6/2 mouse model of Huntington’s disease. Neuroscience 146(4):1571–1580

    CAS  Google Scholar 

  313. Lynch G et al (2007) Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington’s disease. J Neurosci 27(16):4424–4434

    CAS  Google Scholar 

  314. Simmons DA et al (2009) Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington’s disease knockin mice. Proc Natl Acad Sci USA 106(12):4906–4911

    CAS  Google Scholar 

  315. Kilgore M et al (2010) Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 35(4):870–880

    CAS  Google Scholar 

  316. Fontan-Lozano A et al (2008) Histone deacetylase inhibitors improve learning consolidation in young and in KA-induced-neurodegeneration and SAMP-8-mutant mice. Mol Cell Neurosci 39(2):193–201

    CAS  Google Scholar 

  317. Fischer A et al (2007) Recovery of learning and memory is associated with chromatin remodelling. Nature 447(7141):178–182

    CAS  Google Scholar 

  318. Kim D et al (2008) Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60(5):803–817

    CAS  Google Scholar 

  319. Guan JS et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459(7243):55–60

    CAS  Google Scholar 

  320. McKinsey TA, Zhang CL, Olson EN (2000) Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci USA 97(26):14400–14405

    CAS  Google Scholar 

  321. Hardingham GE et al (1997) Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385(6613):260–265

    CAS  Google Scholar 

  322. Chawla S et al (2003) Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J Neurochem 85(1):151–159

    CAS  Google Scholar 

  323. Darcy MJ et al (2010) Regional and subcellular distribution of HDAC4 in mouse brain. J Comp Neurol 518(5):722–740

    CAS  Google Scholar 

  324. Tian X et al (2010) MEF-2 regulates activity-dependent spine loss in striatopallidal medium spiny neurons. Mol Cell Neurosci 44(1):94–108

    CAS  Google Scholar 

  325. Barbosa AC et al (2008) MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc Natl Acad Sci USA 105(27):9391–9396

    CAS  Google Scholar 

  326. Cohen TJ et al (2009) The deacetylase HDAC4 controls myocyte enhancing factor-2-dependent structural gene expression in response to neural activity. FASEB J 23(1):99–106

    CAS  Google Scholar 

  327. Cohen TJ et al (2007) The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming. J Biol Chem 282(46):33752–33759

    CAS  Google Scholar 

  328. Zhang CL, McKinsey TA, Olson EN (2002) Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation. Mol Cell Biol 22(20):7302–7312

    CAS  Google Scholar 

  329. Williams AH et al (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326(5959):1549–1554

    CAS  Google Scholar 

  330. Wuwongse S, Chang RC, Law AC (2010) The putative neurodegenerative links between depression and Alzheimer’s disease. Prog Neurobiol 91(4):362–375

    Google Scholar 

  331. Covington HE III, Vialou V, Nestler EJ (2010) From synapse to nucleus: novel targets for treating depression. Neuropharmacology 58(4–5):683–693

    CAS  Google Scholar 

  332. Tsankova NM et al (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9(4):519–525

    CAS  Google Scholar 

  333. Tsankova N et al (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8(5):355–367

    CAS  Google Scholar 

  334. Renthal W et al (2007) Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56(3):517–529

    CAS  Google Scholar 

  335. Covington HE III et al (2009) Antidepressant actions of histone deacetylase inhibitors. J Neurosci 29(37):11451–11460

    CAS  Google Scholar 

  336. Iga J et al (2007) Altered HDAC5 and CREB mRNA expressions in the peripheral leukocytes of major depression. Prog Neuropsychopharmacol Biol Psychiatry 31(3):628–632

    CAS  Google Scholar 

  337. Hobara T et al (2010) Altered gene expression of histone deacetylases in mood disorder patients. J Psychiatr Res 44(5):263–270

    Google Scholar 

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Authors and Affiliations

  1. BioFocus, Chesterford Research Park, Saffron Walden, Essex, CB10 1XL, UK

    Roland W. Bürli & Elizabeth Thomas

  2. CHDI Foundation, 6080 Center Drive, Los Angeles, CA, 90045, USA

    Vahri Beaumont

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  1. Roland W. Bürli
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  2. Elizabeth Thomas
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Correspondence to Vahri Beaumont .

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  1. CHDI Foundation, Inc., Center Drive 6080, Los Angeles, 90045, California, USA

    Celia Dominguez

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Bürli, R.W., Thomas, E., Beaumont, V. (2010). The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach. In: Dominguez, C. (eds) Neurodegenerative Diseases. Topics in Medicinal Chemistry, vol 6. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2010_10

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