Therapeutic Strategies for Huntington’s Disease

Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 22)

Abstract

Huntington’s disease (HD) is a devastating autosomal dominant neurodegenerative disease, caused by expansion of the CAG repeat in the huntingtin (HTT) gene and characterized pathologically by the loss of pyramidal neurons in several cortical areas, of striatal medium spiny neurons, and of hypothalamic neurons. Clinically, a distinguishing feature of the disease is uncontrolled involuntary movements (chorea, dyskensias) accompanied by progressive cognitive, motor, and psychiatric impairment. This review focuses on the current state of therapeutic development for the treatment of HD, including the preclinical and clinical development of small molecules and molecular therapies.

Keywords

Huntington’s disease Huntingtin CAG repeats Kynurenine PDE HDACs ASO siRNA Zinc-finger repressors Dopamine Glutamate GABA Adenosine 

References

  1. Ahn HS, Bercovici A, Boykow G et al (1997) Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity. J Med Chem 40:2196–2210PubMedGoogle Scholar
  2. Aiken CT, Steffan JS, Guerrero CM et al (2009) Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. J Biol Chem 284:29427–29436PubMedCentralPubMedGoogle Scholar
  3. Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375PubMedGoogle Scholar
  4. Alkondon M, Pereira EF, Yu P et al (2004) Targeted deletion of the kynurenine aminotransferase ii gene reveals a critical role of endogenous kynurenic acid in the regulation of synaptic transmission via alpha7 nicotinic receptors in the hippocampus. J Neurosci 24:4635–4648PubMedGoogle Scholar
  5. Alkondon M, Pereira EF, Albuquerque EX (2011) Endogenous activation of nAChRs and NMDA receptors contributes to the excitability of CA1 stratum radiatum interneurons in rat hippocampal slices: effects of kynurenic acid. Biochem Pharmacol 82:842–851PubMedGoogle Scholar
  6. Allen KL, Waldvogel HJ, Glass M et al (2009) Cannabinoid (CB(1)), GABA(A) and GABA(B) receptor subunit changes in the globus pallidus in Huntington’s disease. J Chem Neuroanat 37:266–281PubMedGoogle Scholar
  7. Andrade MA, Bork P (1995) HEAT repeats in the Huntington’s disease protein. Nat Genet 11:115–116PubMedGoogle Scholar
  8. Andre VM, Cepeda C, Levine MS (2010) Dopamine and glutamate in Huntington’s disease: a balancing act. CNS Neurosci Ther 16:163–178PubMedCentralPubMedGoogle Scholar
  9. Arenas E, Akerud P, Wong V et al (1996) Effects of BDNF and NT-4/5 on striatonigral neuropeptides or nigral GABA neurons in vivo. Eur J Neurosci 8:1707–1717PubMedGoogle Scholar
  10. Arregui L, Benitez JA, Razgado LF et al (2011) Adenoviral astrocyte-specific expression of BDNF in the striata of mice transgenic for Huntington’s disease delays the onset of the motor phenotype. Cell Mol Neurobiol 31:1229–1243PubMedGoogle Scholar
  11. Atwal RS, Desmond CR, Caron N et al (2011) Kinase inhibitors modulate huntingtin cell localization and toxicity. Nat Chem Biol 7:453–460PubMedGoogle Scholar
  12. Baldo B, Paganetti P, Grueninger S et al (2012) TR-FRET-based duplex immunoassay reveals an inverse correlation of soluble and aggregated mutant huntingtin in huntington’s disease. Chem Biol 19:264–275PubMedGoogle Scholar
  13. Bari M, Battista N, Valenza M et al (2013) In vitro and in vivo models of Huntington’s disease show alterations in the endocannabinoid system. FEBS J 280:3376–3388PubMedGoogle Scholar
  14. Bartus RT, Baumann TL, Brown L et al (2013) Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating “clinical proof-of-concept” for AAV-neurturin (CERE-120) in Parkinson’s disease. Neurobiol Aging 34:35–61PubMedGoogle Scholar
  15. Becher MW, Kotzuk JA, Sharp AH et al (1998) Intranuclear neuronal inclusions in Huntington’s disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis 4:387–397PubMedGoogle Scholar
  16. Beconi MG, Yates D, Lyons K et al (2012a) Metabolism and pharmacokinetics of JM6 in mice: JM6 is not a prodrug for Ro-61-8048. Drug Metab Dispos 40:2297–2306PubMedGoogle Scholar
  17. Beconi M, Aziz O, Matthews K et al (2012b) Oral administration of the pimelic diphenylamide HDAC inhibitor HDACi 4b is unsuitable for chronic inhibition of HDAC activity in the CNS in vivo. PLoS One 7:e44498PubMedCentralPubMedGoogle Scholar
  18. Beher D, Wu J, Cumine S et al (2009) Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des 74:619–624PubMedGoogle Scholar
  19. Benn CL, Butler R, Mariner L et al (2009) Genetic knock-down of HDAC7 does not ameliorate disease pathogenesis in the R6/2 mouse model of Huntington’s disease. PLoS One 4:e5747PubMedCentralPubMedGoogle Scholar
  20. Bertolino A, Crippa D, di Dio S et al (1988) Rolipram versus imipramine in inpatients with major, minor or atypical depressive disorder: a double-blind double-dummy study aimed at testing a novel therapeutic approach. Int Clin Psychopharmacol 3:245–253PubMedGoogle Scholar
  21. Besusso D, Geibel M, Kramer D et al (2013) BDNF-TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior. Nat Commun 4:2031PubMedCentralPubMedGoogle Scholar
  22. Biglan KM, Ross CA, Langbehn DR et al (2009) Motor abnormalities in premanifest persons with Huntington’s disease: the PREDICT-HD study. Mov Disord 24:1763–1772PubMedCentralPubMedGoogle Scholar
  23. Blazquez C, Chiarlone A, Sagredo O et al (2011) Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease. Brain 134:119–136PubMedGoogle Scholar
  24. Bobrowska A, Paganetti P, Matthias P et al (2011) Hdac6 knock-out increases tubulin acetylation but does not modify disease progression in the R6/2 mouse model of Huntington’s disease. PLoS One 6:e20696PubMedCentralPubMedGoogle Scholar
  25. Bobrowska A, Donmez G, Weiss A et al (2012) SIRT2 ablation has no effect on tubulin acetylation in brain, cholesterol biosynthesis or the progression of Huntington’s disease phenotypes in vivo. PLoS One 7:e34805PubMedCentralPubMedGoogle Scholar
  26. Boess FG, Hendrix M, van der Staay FJ et al (2004) Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 47:1081–1092PubMedGoogle Scholar
  27. Borowsky B, Warner J, Leavitt BR et al (2013) 8OHdG is not a biomarker for Huntington disease state or progression. Neurology 80:1934–1941PubMedCentralPubMedGoogle Scholar
  28. Borrell-Pages M, Canals JM, Cordelieres FP et al (2006) Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest 116:1410–1424PubMedCentralPubMedGoogle Scholar
  29. Brandt J, Folstein SE, Wong DF et al (1990) D2 receptors in Huntington’s disease: positron emission tomography findings and clinical correlates. J Neuropsychiatry Clin Neurosci 2:20–27PubMedGoogle Scholar
  30. Brito V, Puigdellivol M, Giralt A et al (2013) Imbalance of p75(NTR)/TrkB protein expression in Huntington’s disease: implication for neuroprotective therapies. Cell Death Dis 4:e595PubMedCentralPubMedGoogle Scholar
  31. Bruno O, Fedele E, Prickaerts J et al (2011) GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses. Br J Pharmacol 164:2054–2063PubMedCentralPubMedGoogle Scholar
  32. Buckley NJ, Johnson R, Zuccato C et al (2010) The role of REST in transcriptional and epigenetic dysregulation in Huntington’s disease. Neurobiol Dis 39:28–39PubMedGoogle Scholar
  33. Bureau Y, Handa M, Zhu Y et al (2006) Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6-(4-pyridylmethyl)-8-(3-nitrophenyl) quinoline. Neuropharmacology 51:974–985PubMedGoogle Scholar
  34. Burgin AB, Magnusson OT, Singh J et al (2010) Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 28:63–70PubMedGoogle Scholar
  35. Cachope R (2012) Functional diversity on synaptic plasticity mediated by endocannabinoids. Philos Trans R Soc Lond B Biol Sci 367:3242–3253PubMedCentralPubMedGoogle Scholar
  36. Campesan S, Green EW, Breda C et al (2011) The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Curr Biol 21:961–966PubMedCentralPubMedGoogle Scholar
  37. Canals JM, Pineda JR, Torres-Peraza JF et al (2004) Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J Neurosci 24:7727–7739PubMedGoogle Scholar
  38. Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 6:919–930PubMedGoogle Scholar
  39. Caviston JP, Holzbaur EL (2009) Huntingtin as an essential integrator of intracellular vesicular trafficking. Trends Cell Biol 19:147–155PubMedCentralPubMedGoogle Scholar
  40. Cepeda C, Galvan L, Holley SM et al (2013) Multiple sources of striatal inhibition are differentially affected in Huntington’s disease mouse models. J Neurosci 33:7393–7406PubMedCentralPubMedGoogle Scholar
  41. Chandrasekaran A, Toh KY, Low SH et al (2008) Identification and characterization of novel mouse PDE4D isoforms: Molecular cloning, subcellular distribution and detection of isoform-specific intracellular localization signals. Cell Signal 20:139–153PubMedGoogle Scholar
  42. Chaturvedi RK, Beal MF (2013) Mitochondria targeted therapeutic approaches in Parkinson’s and Huntington’s diseases. Mol Cell Neurosci 55:101–114PubMedGoogle Scholar
  43. Chaturvedi RK, Adhihetty P, Shukla S et al (2009) Impaired PGC-1alpha function in muscle in Huntington’s disease. Hum Mol Genet 18:3048–3065PubMedCentralPubMedGoogle Scholar
  44. Chen JJ, Ondo WG, Dashtipour K et al (2012) Tetrabenazine for the treatment of hyperkinetic movement disorders: a review of the literature. Clin Ther 34:1487–1504PubMedGoogle Scholar
  45. Chiodi V, Uchigashima M, Beggiato S et al (2012) Unbalance of CB1 receptors expressed in GABAergic and glutamatergic neurons in a transgenic mouse model of Huntington’s disease. Neurobiol Dis 45:983–991PubMedGoogle Scholar
  46. Chou SY, Lee YC, Chen HM et al (2005) CGS21680 attenuates symptoms of Huntington’s disease in a transgenic mouse model. J Neurochem 93:310–320PubMedGoogle Scholar
  47. Choudhary C, Kumar C, Gnad F et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840PubMedGoogle Scholar
  48. Christofides J, Bridel M, Egerton M et al (2006) Blood 5-hydroxytryptamine, 5-hydroxyindoleacetic acid and melatonin levels in patients with either Huntington’s disease or chronic brain injury. J Neurochem 97:1078–1088PubMedGoogle Scholar
  49. Ciammola A, Sassone J, Sciacco M et al (2011) Low anaerobic threshold and increased skeletal muscle lactate production in subjects with Huntington’s disease. Mov Disord 26:130–137PubMedCentralPubMedGoogle Scholar
  50. Conforti P (2013) Mas Monteys, A.; Zuccato, C., et al. In vivo delivery of DN:REST improves transcriptional changes of REST-regulated genes in HD mice. Gene Ther 20:678–685PubMedGoogle Scholar
  51. Conforti P, Zuccato C, Gaudenzi G et al (2013) Binding of the repressor complex REST-mSIN3b by small molecules restores neuronal gene transcription in Huntington’s disease models. J Neurochem 127(1):22–35Google Scholar
  52. Crook ZR, Housman D (2011) Huntington’s disease: can mice lead the way to treatment? Neuron 69:423–435PubMedGoogle Scholar
  53. Curtis A, Mitchell I, Patel S et al (2009) A pilot study using nabilone for symptomatic treatment in Huntington’s disease. Mov Disord 24:2254–2259PubMedGoogle Scholar
  54. Dai H, Kustigian L, Carney D et al (2010) SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator. J Biol Chem 285:32695–32703PubMedCentralPubMedGoogle Scholar
  55. De Chiara V, Angelucci F, Rossi S et al (2010) Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum. J Neurosci 30:8127–8137PubMedGoogle Scholar
  56. De Yebenes JG, Landwehrmeyer B, Squitieri F et al (2011) Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol 10:1049–1057PubMedGoogle Scholar
  57. Demarch Z, Giampa C, Patassini S et al (2007) Beneficial effects of rolipram in a quinolinic acid model of striatal excitotoxicity. Neurobiol Dis 25:266–273PubMedGoogle Scholar
  58. DeMarch Z, Giampa C, Patassini S et al (2008) Beneficial effects of rolipram in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 30:375–387PubMedGoogle Scholar
  59. Denovan-Wright EM, Robertson HA (2000) Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington’s disease mice. Neuroscience 98:705–713PubMedGoogle Scholar
  60. Deuschl G, Schade-Brittinger C, Krack P et al (2006) A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 355:896–908PubMedGoogle Scholar
  61. Domenici MR, Scattoni ML, Martire A et al (2007) Behavioral and electrophysiological effects of the adenosine A2A receptor antagonist SCH 58261 in R6/2 Huntington’s disease mice. Neurobiol Dis 28:197–205PubMedGoogle Scholar
  62. Doria JG, Silva FR, de Souza JM et al (2013) Metabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington’s disease. Br J Pharmacol 169:909–921PubMedCentralPubMedGoogle Scholar
  63. Dowie MJ, Bradshaw HB, Howard ML et al (2009) Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington’s disease. Neuroscience 163:456–465PubMedGoogle Scholar
  64. Dowie MJ, Howard ML, Nicholson LF et al (2010) Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington’s disease transgenic mice. Neuroscience 170:324–336PubMedGoogle Scholar
  65. Dubinsky R, Gray C (2006) CYTE-I-HD: phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington’s disease. Mov Disord 21:530–533PubMedGoogle Scholar
  66. Duff K, Paulsen JS, Beglinger LJ et al (2007) Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry 62:1341–1346PubMedGoogle Scholar
  67. Duff K, Paulsen JS, Beglinger LJ et al (2010) Frontal behaviors before the diagnosis of Huntington’s disease and their relationship to markers of disease progression: evidence of early lack of awareness. J Neuropsychiatry Clin Neurosci 22:196–207PubMedCentralPubMedGoogle Scholar
  68. Dyhring T, Nielsen EO, Sonesson C et al (2010) The dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties. Eur J Pharmacol 628:19–26PubMedGoogle Scholar
  69. Ehrnhoefer DE, Sutton L, Hayden MR (2011) Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. Neuroscientist 17:475–492PubMedCentralPubMedGoogle Scholar
  70. Eidelberg D, Surmeier DJ (2011) Brain networks in Huntington disease. J Clin Invest 121:484–492PubMedCentralPubMedGoogle Scholar
  71. Faideau M, Kim J, Cormier K et al (2010) In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington’s disease subjects. Hum Mol Genet 19:3053–3067PubMedCentralPubMedGoogle Scholar
  72. Fasano A, Mazzone P, Piano C et al (2008) GPi-DBS in Huntington’s disease: results on motor function and cognition in a 72-year-old case. Mov Disord 23:1289–1292PubMedGoogle Scholar
  73. Fawcett AP, Moro E, Lang AE et al (2005) Pallidal deep brain stimulation influences both reflexive and voluntary saccades in Huntington’s disease. Mov Disord 20:371–377PubMedGoogle Scholar
  74. Ferrante A, Martire A, Armida M et al (2010) Influence of CGS 21680, a selective adenosine A(2A) receptor agonist, on NMDA receptor function and expression in the brain of Huntington’s disease mice. Brain Res 1323:184–191PubMedGoogle Scholar
  75. Figiel M, Szlachcic WJ, Switonski PM et al (2012) Mouse models of polyglutamine diseases: review and data table. Part I. Mol Neurobiol 46:393–429Google Scholar
  76. Fischbeck KH (2001) Polyglutamine expansion neurodegenerative disease. Brain Res Bull 56:161–163PubMedGoogle Scholar
  77. Fletcher JM, Hughes RA (2009) Modified low molecular weight cyclic peptides as mimetics of BDNF with improved potency, proteolytic stability and transmembrane passage in vitro. Bioorg Med Chem 17:2695–2702PubMedGoogle Scholar
  78. Folstein SE, Chase GA, Wahl WE et al (1987) Huntington disease in Maryland: clinical aspects of racial variation. Am J Hum Genet 41:168–179PubMedCentralPubMedGoogle Scholar
  79. Forrest CM, Mackay GM, Stoy N et al (2010) Blood levels of kynurenines, interleukin-23 and soluble human leucocyte antigen-G at different stages of Huntington’s disease. J Neurochem 112:112–122PubMedGoogle Scholar
  80. Frank S (2010) Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease. Neuropsychiatr Dis Treat 6:657–665PubMedCentralPubMedGoogle Scholar
  81. Frank S, Ondo W, Fahn S et al (2008) A study of chorea after tetrabenazine withdrawal in patients with Huntington disease. Clin Neuropharmacol 31:127–133PubMedGoogle Scholar
  82. Gellerich FN, Gizatullina Z, Nguyen HP et al (2008) Impaired regulation of brain mitochondria by extramitochondrial Ca2 + in transgenic Huntington disease rats. J Biol Chem 283:30715–30724PubMedCentralPubMedGoogle Scholar
  83. Gertz M, Fischer F, Nguyen GT et al (2013) Ex-527 inhibits Sirtuins by exploiting their unique NAD + -dependent deacetylation mechanism. Proc Natl Acad Sci U S A 110(30):E2772–781Google Scholar
  84. Giampa C, Laurenti D, Anzilotti S et al (2010) Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington’s disease. PLoS One 5:e13417PubMedCentralPubMedGoogle Scholar
  85. Giampa C, Montagna E, Dato C et al (2013) Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington’s disease. PLoS One 8:e64037PubMedCentralPubMedGoogle Scholar
  86. Giampà C, DeMarch Z, D’Angelo V et al (2006) Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions: implications with neuronal vulnerability in Huntington’s disease. Eur J Neurosci 23:11–20PubMedGoogle Scholar
  87. Giampà C, Patassini S, Borreca A et al (2009a) Phosphodiesterase 10 inhibition reduces striatal excitotoxicity in the quinolinic acid model of Huntington’s disease. Neurobiol Dis 34:450–456PubMedGoogle Scholar
  88. Giampà C, Middei S, Patassini S et al (2009b) Phosphodiesterase type IV inhibition prevents sequestration of CREB binding protein, protects striatal parvalbumin interneurons and rescues motor deficits in the R6/2 mouse model of Huntington’s disease. Eur J Neurosci 29:902–910PubMedGoogle Scholar
  89. Gines S (2003) Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington’s disease knock-in mice. Hum Mol Genet 12:497–508PubMedGoogle Scholar
  90. Giralt A, Saavedra A, Carreton O et al (2011) Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington’s disease. Hum Mol Genet 20(21):4232–4247Google Scholar
  91. Giralt A, Carreton O, Lao-Peregrin C et al (2011b) Conditional BDNF release under pathological conditions improves Huntington’s disease pathology by delaying neuronal dysfunction. Mol Neurodegener 6:71PubMedCentralPubMedGoogle Scholar
  92. Glass M, Faull RL, Dragunow M (1993) Loss of cannabinoid receptors in the substantia nigra in Huntington’s disease. Neuroscience 56:523–527PubMedGoogle Scholar
  93. Glass M, Dragunow M, Faull RL (2000) The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience 97:505–519PubMedGoogle Scholar
  94. Goggi J, Pullar IA, Carney SL et al (2002) Modulation of neurotransmitter release induced by brain-derived neurotrophic factor in rat brain striatal slices in vitro. Brain Res 941:34–42PubMedGoogle Scholar
  95. Gray MA, Egan GF, Ando A et al (2013) Prefrontal activity in Huntington’s disease reflects cognitive and neuropsychiatric disturbances: the IMAGE-HD study. Exp Neurol 239:218–228PubMedGoogle Scholar
  96. Grondin R, Kaytor MD, Ai Y et al (2012) Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 135:1197–1209PubMedCentralPubMedGoogle Scholar
  97. Gu X, Li C, Wei W et al (2005) Pathological cell–cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice. Neuron 46:433–444PubMedGoogle Scholar
  98. Guenther MG, Barak O, Lazar MA (2001) The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol 21:6091–6101PubMedCentralPubMedGoogle Scholar
  99. Guidetti P, Reddy PH, Tagle DA et al (2000) Early kynurenergic impairment in Huntington’s disease and in a transgenic animal model. Neurosci Lett 283:233–235PubMedGoogle Scholar
  100. Guidetti P, Luthi-Carter RE, Augood SJ et al (2004) Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiol Dis 17:455–461PubMedGoogle Scholar
  101. Guidetti P, Bates GP, Graham RK et al (2006) Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Neurobiol Dis 23:190–197PubMedGoogle Scholar
  102. Hall JA, Dominy JE, Lee Y et al (2013) The sirtuin family’s role in aging and age-associated pathologies. J Clin Invest 123:973–979PubMedCentralPubMedGoogle Scholar
  103. Handa N, Mizohata E, Kishishita S et al (2008) Crystal Structure of the GAF-B Domain from Human Phosphodiesterase 10A Complexed with Its Ligand, cAMP. J Biol Chem 283:19657–19664PubMedGoogle Scholar
  104. Haroon E, Raison CL, Miller AH (2012) Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 37:137–162PubMedCentralPubMedGoogle Scholar
  105. Hassel B, Tessler S, Faull RL et al (2008) Glutamate uptake is reduced in prefrontal cortex in Huntington’s disease. Neurochem Res 33:232–237PubMedGoogle Scholar
  106. Hauser RA, Cantillon M, Pourcher E et al (2011) Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol 10:221–229PubMedGoogle Scholar
  107. Hayden MR, MacGregor JM, Beighton PH (1980) The prevalence of Huntington’s chorea in South Africa. S Afr Med J 58:193–196PubMedGoogle Scholar
  108. Hebb A, Robertson H (2007) Role of phosphodiesterases in neurological and psychiatric disease. Curr Opin Pharmacol 7:86–92PubMedGoogle Scholar
  109. Hebb MO, Garcia R, Gaudet P et al (2006) Bilateral stimulation of the globus pallidus internus to treat choreathetosis in Huntington’s disease: technical case report. Neurosurgery 58:E383.discussion E383Google Scholar
  110. Hebenstreit GF, Fellerer K, Fichte K et al (1989) Rolipram in major depressive disorder: results of a double-blind comparative study with imipramine. Pharmacopsychiatry 22:156–160PubMedGoogle Scholar
  111. Heikkinen T, Lehtimaki K, Vartiainen N et al (2012) Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington’s disease. PLoS One 7:e50717PubMedCentralPubMedGoogle Scholar
  112. Hersch SM, Gevorkian S, Marder K et al (2006) Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG. Neurology 66:250–252PubMedGoogle Scholar
  113. Hickey MA, Zhu C, Medvedeva V et al (2012) Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington’s disease. Mol Cell Neurosci 49:149–157PubMedCentralPubMedGoogle Scholar
  114. Hilditch-Maguire P, Trettel F, Passani LA et al (2000) Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet 9:2789–2797PubMedGoogle Scholar
  115. Ho DJ, Calingasan NY, Wille E et al (2010) Resveratrol protects against peripheral deficits in a mouse model of Huntington’s disease. Exp Neurol 225:74–84PubMedGoogle Scholar
  116. Hockly E, Richon VM, Woodman B 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 U S A 100:2041–2046PubMedCentralPubMedGoogle Scholar
  117. Hogel M, Laprairie RB, Denovan-Wright EM (2012) Promoters are differentially sensitive to N-terminal mutant huntingtin-mediated transcriptional repression. PLoS One 7:e41152PubMedCentralPubMedGoogle Scholar
  118. Horne EA, Coy J, Swinney K et al (2013) Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington’s disease and mouse models. Eur J Neurosci 37:429–440PubMedCentralPubMedGoogle Scholar
  119. Houslay MD, Schafer P, Zhang KYJ (2005) Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discovery Today 10:1503–1519PubMedGoogle Scholar
  120. Huang Z, Dias R, Jones T et al (2007) L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition. Biochem Pharmacol 73:1971–1981PubMedGoogle Scholar
  121. Hubbard BP, Loh C, Gomes AP et al (2013) Carboxamide SIRT1 inhibitors block DBC1 binding via an acetylation-independent mechanism. Cell Cycle 12(14):2233–2240. doi:10.4161/cc.25268 Google Scholar
  122. Hult S, Schultz K, Soylu R et al (2010) Hypothalamic and neuroendocrine changes in Huntington’s disease. Curr Drug Targets 11:1237–1249PubMedGoogle Scholar
  123. Hunter A, Bordelon Y, Cook I et al. (2010) QEEG measures in Huntington’s disease: a pilot study. PLoS Curr 2:RRN1192Google Scholar
  124. Huntington Study Group (2001) A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 57:397–404Google Scholar
  125. Huntington Study Group (2006) Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 66:366–372Google Scholar
  126. Huntington Study Group TREND-HD Investigators (2008) Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study. Arch Neurol 65:1582–1589Google Scholar
  127. Huys D, Bartsch C, Poppe P et al (2013) Management and outcome of pallidal deep brain stimulation in severe Huntington’s disease. Fortschr Neurol Psychiatr 81:202–205PubMedGoogle Scholar
  128. Hyson HC, Kieburtz K, Shoulson I et al (2010) Safety and tolerability of high-dosage coenzyme Q10 in Huntington’s disease and healthy subjects. Mov Disord 25:1924–1928PubMedGoogle Scholar
  129. Imanishi T, Sawa A, Ichimaru Y et al (1997) Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents. Eur J Pharmacol 321:273–278PubMedGoogle Scholar
  130. Iona S, Cuomo M, Bushnik T et al (1998) Characterization of the rolipram-sensitive, cyclic AMP-specific phosphodiesterases: identification and differential expression of immunologically distinct forms in the rat brain. Mol Pharmacol 53:23–32PubMedGoogle Scholar
  131. Ivkovic S, Ehrlich ME (1999) Expression of the striatal DARPP-32/ARPP-21 phenotype in GABAergic neurons requires neurotrophins in vivo and in vitro. J Neurosci 19:5409–5419PubMedGoogle Scholar
  132. Jenkins BG, Rosas HD, Chen YC et al (1998) 1H NMR spectroscopy studies of Huntington’s disease: correlations with CAG repeat numbers. Neurology 50:1357–1365PubMedGoogle Scholar
  133. Jeon YH, Heo YS, Kim CM et al (2005) Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development. Cell Mol Life Sci 62:1198–1220PubMedGoogle Scholar
  134. Jeong H, Then F, Melia TJ Jr et al (2009) Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137:60–72PubMedCentralPubMedGoogle Scholar
  135. Jeong H, Cohen DE, Cui L et al (2012) Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 18:159–165Google Scholar
  136. Jia H, Kast RJ, Steffan JS et al (2012a) Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington’s disease mice: implications for the ubiquitin-proteasomal and autophagy systems. Hum Mol Genet 21:5280–5293PubMedCentralPubMedGoogle Scholar
  137. Jia H, Pallos J, Jacques V et al (2012b) Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington’s disease. Neurobiol Dis 46:351–361PubMedCentralPubMedGoogle Scholar
  138. Jiang M, Wang J, Fu J et al (2012) Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 18:153–158Google Scholar
  139. Jiang M, Peng Q, Liu X et al (2013) Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington’s disease. Hum Mol Genet 22:2462–2470PubMedCentralPubMedGoogle Scholar
  140. Jiao Y, Zhang Z, Zhang C et al (2011) A key mechanism underlying sensory experience-dependent maturation of neocortical GABAergic circuits in vivo. Proc Natl Acad Sci U S A 108:12131–12136PubMedCentralPubMedGoogle Scholar
  141. Jin J, Albertz J, Guo Z et al (2013) Neuroprotective effects of PPAR-gamma agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease. J Neurochem 125:410–419PubMedCentralPubMedGoogle Scholar
  142. Johnson JA, Johnson DA, Kraft AD et al (2008) The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Ann N Y Acad Sci 1147:61–69PubMedCentralPubMedGoogle Scholar
  143. Johri A, Calingasan NY, Hennessey TM et al (2012) Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Hum Mol Genet 21:1124–1137PubMedCentralPubMedGoogle Scholar
  144. Jovicic A, Zaldivar Jolissaint JF, Moser R et al (2013) MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington’s disease-related mechanisms. PLoS One 8:e54222Google Scholar
  145. Kang GA, Heath S, Rothlind J et al (2011) Long-term follow-up of pallidal deep brain stimulation in two cases of Huntington’s disease. J Neurol Neurosurg Psychiatry 82:272–277PubMedGoogle Scholar
  146. Kara E, Lin H, Svensson K et al (2010) Analysis of the actions of the novel dopamine receptor-directed compounds (S)-OSU6162 and ACR16 at the D2 dopamine receptor. Br J Pharmacol 161:1343–1350PubMedCentralPubMedGoogle Scholar
  147. Kegel KB, Sapp E, Alexander J et al (2009) Polyglutamine expansion in huntingtin alters its interaction with phospholipids. J Neurochem 110:1585–1597PubMedGoogle Scholar
  148. Kells AP, Fong DM, Dragunow M et al (2004) AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol Ther 9:682–688PubMedGoogle Scholar
  149. Khoshnan A, Patterson PH (2011) The role of IkappaB kinase complex in the neurobiology of Huntington’s disease. Neurobiol Dis 43:305–311PubMedCentralPubMedGoogle Scholar
  150. Kim J, Amante DJ, Moody JP et al (2010) Reduced creatine kinase as a central and peripheral biomarker in Huntington’s disease. Biochim Biophys Acta 1802:673–681PubMedCentralPubMedGoogle Scholar
  151. Kleiman RJ, Kimmel LH, Bove SE et al (2010) Chronic suppression of phosphodiesterase 10A alters striatal expression of Genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington’s disease. J Pharmacol Exp Ther 336:64–76PubMedGoogle Scholar
  152. Kleiman RJ, Kimmel LH, Bove SE et al (2011) Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington’s disease. J Pharmacol Exp Ther 336:64–76PubMedGoogle Scholar
  153. Kobayashi M, Kubo S, Iwata M et al (2011) ASP3258, an orally active potent phosphodiesterase 4 inhibitor with low emetic activity. Int Immunopharmacol 11:732–739PubMedGoogle Scholar
  154. Konradsson-Geuken A, Wu HQ, Gash CR et al (2010) Cortical kynurenic acid bi-directionally modulates prefrontal glutamate levels as assessed by microdialysis and rapid electrochemistry. Neuroscience 169:1848–1859PubMedCentralPubMedGoogle Scholar
  155. Kordasiewicz HB, Stanek LM, Wancewicz EV et al (2012) Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74:1031–1044PubMedCentralPubMedGoogle Scholar
  156. Kotera J (2003) Subcellular localization of cyclic nucleotide phosphodiesterase type 10A variants, and alteration of the localization by cAMP-dependent protein kinase-dependent phosphorylation. J Biol Chem 279:4366–4375PubMedGoogle Scholar
  157. Kuroiwa M, Snyder GL, Shuto T et al (2011) Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. Psychopharmacology (Berl) 25(8):1101–1117Google Scholar
  158. La Spada AR (2012) Finding a sirtuin truth in Huntington’s disease. Nat Med 18:24–26PubMedGoogle Scholar
  159. Landwehrmeyer GB, Dubois B, de Yebenes JG et al (2007) Riluzole in Huntington’s disease: a 3-year, randomized controlled study. Ann Neurol 62:262–272PubMedGoogle Scholar
  160. Langbehn DR, Hayden MR, Paulsen JS (2010) CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. Am J Med Genet B Neuropsychiatr Genet 153B:397–408PubMedCentralPubMedGoogle Scholar
  161. Lastres-Becker I, Berrendero F, Lucas JJ et al (2002) Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington’s disease. Brain Res 929:236–242PubMedGoogle Scholar
  162. Lemtiri-Chlieh F, Levine ES (2010) BDNF evokes release of endogenous cannabinoids at layer 2/3 inhibitory synapses in the neocortex. J Neurophysiol 104:1923–1932PubMedCentralPubMedGoogle Scholar
  163. Li YF, Cheng YF, Huang Y et al (2011) Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci 31:172–183PubMedCentralPubMedGoogle Scholar
  164. Ligot N, Krystkowiak P, Simonin C et al (2011) External globus pallidus stimulation modulates brain connectivity in Huntington’s disease. J Cereb Blood Flow Metab 31:41–46PubMedCentralPubMedGoogle Scholar
  165. Lin YS, Chen CM, Soong BW et al (2011) Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease. J Clin Invest 121:1519–1523PubMedCentralPubMedGoogle Scholar
  166. Liot G, Zala D, Pla P et al (2013) Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J Neurosci 33:6298–6309PubMedGoogle Scholar
  167. Lopes C, Pereira EF, Wu HQ et al (2007) Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors. J Pharmacol Exp Ther 322:48–58PubMedGoogle Scholar
  168. Lundin A, Dietrichs E, Haghighi S et al (2010) Efficacy and safety of the dopaminergic stabilizer Pridopidine (ACR16) in patients with Huntington’s disease. Clin Neuropharmacol 33:260–264PubMedGoogle Scholar
  169. Luthi-Carter R, Taylor DM, Pallos J et al (2010) SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci U S A 107:7927–7932PubMedCentralPubMedGoogle Scholar
  170. Margolis RL, Ross CA (2001) Expansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases. Trends Mol Med 7:479–482PubMedGoogle Scholar
  171. Marongiu D, Imbrosci B, Mittmann T (2013) Modulatory effects of the novel TrkB receptor agonist 7,8-dihydroxyflavone on synaptic transmission and intrinsic neuronal excitability in mouse visual cortex in vitro. Eur J Pharmacol 709:64–71PubMedGoogle Scholar
  172. Martin-Aparicio E, Yamamoto A, Hernandez F et al (2001) Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington’s disease. J Neurosci 21:8772–8781PubMedGoogle Scholar
  173. Martire A, Ferrante A, Potenza RL et al (2010) Remodeling of striatal NMDA receptors by chronic A(2A) receptor blockade in Huntington’s disease mice. Neurobiol Dis 37:99–105PubMedGoogle Scholar
  174. Martire A, Pepponi R, Domenici MR et al (2013) BDNF prevents NMDA-induced toxicity in models of Huntington’s disease: the effects are genotype specific and adenosine A(2A) receptor is involved. J Neurochem doi:10.1111/jnc.12177
  175. Massa SM, Yang T, Xie Y et al (2010) Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest 120:1774–1785PubMedCentralPubMedGoogle Scholar
  176. Mazarei G, Budac DP, Lu G et al (2013) Age-dependent alterations of the kynurenine pathway in the YAC128 mouse model of Huntington disease. J Neurochem doi: 10.1111/jnc.12350Google Scholar
  177. McFarland KN, Das S, Sun TT et al (2012) Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington’s disease. PLoS One 7:e41423PubMedCentralPubMedGoogle Scholar
  178. Mehvar R, Jamali F, Watson MW et al (1987) Pharmacokinetics of tetrabenazine and its major metabolite in man and rat: Bioavailability and dose dependency studies. Drug Metab Dispos 15:250–255PubMedGoogle Scholar
  179. Menalled LB, Patry M, Ragland N 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:e9793PubMedCentralPubMedGoogle Scholar
  180. Mielcarek M, Benn CL, Franklin SA et al (2011) SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington’s disease. PLoS One 6:e27746PubMedCentralPubMedGoogle Scholar
  181. Mievis S, Blum D, Ledent C (2011) Worsening of Huntington disease phenotype in CB1 receptor knockout mice. Neurobiol Dis 42:524–529PubMedGoogle Scholar
  182. Miller JP, Hughes RE (2011) Protein interactions and target discovery in Huntington’s disease. In: Lo DC, Hughes RE (eds) Neurobiology of Huntington’s disease. Applications to drug discovery. CRC, Boca RatonGoogle Scholar
  183. Miller BR, Dorner JL, Bunner KD et al (2012) Up-regulation of GLT1 reverses the deficit in cortically evoked striatal ascorbate efflux in the R6/2 mouse model of Huntington’s disease. J Neurochem 121:629–638PubMedCentralPubMedGoogle Scholar
  184. Milnerwood AJ, Kaufman AM, Sepers MD et al (2012) Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington’s disease mice. Neurobiol Dis 48:40–51PubMedGoogle Scholar
  185. Mishra R, Hoop CL, Kodali R et al (2012) Serine phosphorylation suppresses huntingtin amyloid accumulation by altering protein aggregation properties. J Mol Biol 424:1–14PubMedCentralPubMedGoogle Scholar
  186. Mitchell CJ, Ballantine SP, Coe DM et al (2010) Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR. Bioorg Med Chem Lett 20:5803–5806PubMedGoogle Scholar
  187. Miyake N, Skinbjerg M, Easwaramoorthy B et al (2011) Imaging changes in glutamate transmission in vivo with the metabotropic glutamate receptor 5 tracer [11C] ABP688 and N-acetylcysteine challenge. Biol Psychiatry 69:822–824PubMedGoogle Scholar
  188. Mizuno Y, Hasegawa K, Kondo T et al (2010) Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Mov Disord 25:1437–1443PubMedGoogle Scholar
  189. Mochel F, Haller RG (2011) Energy deficit in Huntington disease: why it matters. J Clin Invest 121:493–499PubMedCentralPubMedGoogle Scholar
  190. Mochel F, Duteil S, Marelli C et al (2010) Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington’s disease. Eur J Hum Genet 18:1057–1060PubMedCentralPubMedGoogle Scholar
  191. Mochel F, Durant B, Meng X et al (2012) Early alterations of brain cellular energy homeostasis in Huntington disease models. J Biol Chem 287:1361–1370PubMedCentralPubMedGoogle Scholar
  192. Mok MH, Fricker AC, Weil A et al (2009) Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels. Neuropharmacology 57:242–249PubMedGoogle Scholar
  193. Moro E, Lang AE, Strafella AP et al (2004) Bilateral globus pallidus stimulation for Huntington’s disease. Ann Neurol 56:290–294PubMedGoogle Scholar
  194. Moumne L, Campbell K, Howland D et al (2012) Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington’s disease. PLoS One 7:e31080PubMedCentralPubMedGoogle Scholar
  195. Munoz-Sanjuan I, Bates GP (2011) The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease. J Clin Invest 121:476–483PubMedCentralPubMedGoogle Scholar
  196. Nagakura A, Niimura M, Takeo S (2002) Effects of a phosphodiesterase IV inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cyclic AMP signal transduction system in rats. Br J Pharmacol 135:1783–1793PubMedCentralPubMedGoogle Scholar
  197. Naganuma K, Omura A, Maekawara N et al (2009) Discovery of selective PDE4B inhibitors. Bioorg Med Chem Lett 19:3174–3176PubMedGoogle Scholar
  198. Nin V, Escande C, Chini CC et al (2012) Role of deleted in breast cancer 1 (DBC1) protein in SIRT1 deacetylase activation induced by protein kinase A and AMP-activated protein kinase. J Biol Chem 287:23489–23501PubMedCentralPubMedGoogle Scholar
  199. Nishi A, Watanabe Y, Higashi H et al (2005) Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades. Proc Natl Acad Sci U S A 102:1199–1204PubMedCentralPubMedGoogle Scholar
  200. Obrietan K (2004) CRE-mediated transcription is increased in Huntington’s disease transgenic mice. J Neurosci 24:791–796PubMedGoogle Scholar
  201. Okuda S, Nishiyama N, Saito H et al (1998) 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem 70:299–307PubMedGoogle Scholar
  202. O’Leary PD, Hughes RA (2003) Design of potent peptide mimetics of brain-derived neurotrophic factor. J Biol Chem 278:25738–25744PubMedGoogle Scholar
  203. Orru M, Zanoveli JM, Quiroz C et al (2011a) Functional changes in postsynaptic adenosine A(2A) receptors during early stages of a rat model of Huntington disease. Exp Neurol 232:76–80PubMedCentralPubMedGoogle Scholar
  204. Orru M, Bakesova J, Brugarolas M et al (2011b) Striatal pre- and postsynaptic profile of adenosine A(2A) receptor antagonists. PLoS One 6:e16088PubMedCentralPubMedGoogle Scholar
  205. Paleacu D (2007) Tetrabenazine in the treatment of Huntington’s disease. Neuropsychiatr Dis Treat 3:545–551PubMedCentralPubMedGoogle Scholar
  206. Perreault M, Feng G, Will S et al (2013) Activation of TrkB with TAM-163 results in opposite effects on body weight in rodents and non-human primates. PLoS One 8:e62616PubMedCentralPubMedGoogle Scholar
  207. Pettibone DJ, Totaro JA, Pflueger AB (1984a) Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants. Eur J Pharmacol 102:425–430PubMedGoogle Scholar
  208. Pettibone DJ, Pflueger AB, Totaro JA (1984b) Tetrabenazine-induced depletion of brain monoamines: mechanism by which desmethylimipramine protects cortical norepinephrine. Eur J Pharmacol 102:431–436PubMedGoogle Scholar
  209. Pisani A, Bernardi G, Ding J et al (2007) Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci 30:545–553PubMedGoogle Scholar
  210. Pocivavsek A, Wu HQ, Potter MC et al (2011) Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology 36:2357–2367PubMedCentralPubMedGoogle Scholar
  211. Ponten H, Kullingsjo J, Lagerkvist S et al (2010) In vivo pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol 644:88–95PubMedGoogle Scholar
  212. Popoli P, Blum D, Domenici MR et al (2008) A critical evaluation of adenosine A2A receptors as potentially druggable targets in Huntington’s disease. Curr Pharm Des 14:1500–1511PubMedGoogle Scholar
  213. Puri BK, Bydder GM, Counsell SJ et al (2002) MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment. Neuroreport 13:123–126PubMedGoogle Scholar
  214. Puri BK, Leavitt BR, Hayden MR et al (2005) Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial. Neurology 65:286–292PubMedGoogle Scholar
  215. Qin ZH, Wang Y, Sapp E et al (2004) Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J Neurosci 24:269–281PubMedGoogle Scholar
  216. Quinti L, Chopra V, Rotili D et al (2010) Evaluation of histone deacetylases as drug targets in Huntington’s disease models: study of HDACs in brain tissues from R6/2 and CAG140 knock-in HD mouse models and human patients and in a neuronal HD cell model. PLoS Curr 2: pii:RRN1172Google Scholar
  217. Raynes R, Pombier KM, Nguyen K et al (2013) The SIRT1 modulators AROS and DBC1 regulate HSF1 activity and the heat shock response. PLoS One 8:e54364PubMedCentralPubMedGoogle Scholar
  218. Reiner A, Dragatsis I, Zeitlin S et al (2003) Wild-type huntingtin plays a role in brain development and neuronal survival. Mol Neurobiol 28:259–276PubMedGoogle Scholar
  219. Reiner A, Lafferty DC, Wang HB et al (2012) The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington’s disease mice. Neurobiol Dis 47:75–91PubMedCentralPubMedGoogle Scholar
  220. Reynolds NC, Prost RW, Mark LP et al (2008) MR-spectroscopic findings in juvenile-onset Huntington’s disease. Mov Disord 23:1931–1935PubMedGoogle Scholar
  221. Ribeiro FM, Paquet M, Ferreira LT et al (2010) Metabotropic glutamate receptor-mediated cell signaling pathways are altered in a mouse model of Huntington’s disease. J Neurosci 30:316–324PubMedGoogle Scholar
  222. Richfield EK, Herkenham M (1994) Selective vulnerability in Huntington’s disease: preferential loss of cannabinoid receptors in lateral globus pallidus. Ann Neurol 36:577–584PubMedGoogle Scholar
  223. Roberts MS, McLean S, Millingen KS et al (1986) The pharmacokinetics of tetrabenazine and its hydroxy metabolite in patients treated for involuntary movement disorders. Eur J Clin Pharmacol 29:703–708PubMedGoogle Scholar
  224. Robichaud A, Tattersall FD, Choudhury I et al (1999) Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret. Neuropharmacology 38:289–297PubMedGoogle Scholar
  225. Robichaud A, Savoie C, Stamatiou PB et al (2002) Assessing the emetic potential of PDE4 inhibitors in rats. Br J Pharmacol 135:113–118PubMedCentralPubMedGoogle Scholar
  226. Rodefer JS, Saland SK, Eckrich SJ (2012) Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats. Neuropharmacology 62(3):1182-1190Google Scholar
  227. Rose GM, Hopper A, De Vivo M et al (2005) Phosphodiesterase inhibitors for cognitive enhancement. Curr Pharm Des 11:3329–3334PubMedGoogle Scholar
  228. Ross CA, Tabrizi SJ (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10:83–98PubMedGoogle Scholar
  229. Rung JP, Rung E, Helgeson L et al (2008) Effects of (-)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization. J Neural Transm 115:899–908PubMedGoogle Scholar
  230. Rutten K, Prickaerts J, Blokland A (2006) Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action. Neurobiol Learn Mem 85:132–138PubMedGoogle Scholar
  231. Rutten K, Lieben C, Smits L et al (2007a) The PDE4 inhibitor rolipram reverses object memory impairment induced by acute tryptophan depletion in the rat. Psychopharmacology (Berl) 192:275–282Google Scholar
  232. Rutten K, Prickaerts J, Hendrix M et al (2007b) Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. Eur J Pharmacol 558:107–112PubMedGoogle Scholar
  233. Rutten K, Basile JL, Prickaerts J et al (2008) Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques. Psychopharmacology (Berl) 196:643–648Google Scholar
  234. Sadri-Vakili G, Bouzou B, Benn CL et al (2007) Histones associated with downregulated genes are hypo-acetylated in Huntington’s disease models. Hum Mol Genet 16:1293–1306PubMedGoogle Scholar
  235. Sah DW, Aronin N (2011) Oligonucleotide therapeutic approaches for Huntington disease. J Clin Invest 121:500–507PubMedCentralPubMedGoogle Scholar
  236. Sanberg PR, Fibiger HC, Mark RF (1981) Body weight and dietary factors in Huntington’s disease patients compared with matched controls. Med J Aust 1:407–409PubMedGoogle Scholar
  237. Sapko MT, Guidetti P, Yu P et al (2006) Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: Implications for Huntington’s disease. Exp Neurol 197:31–40PubMedGoogle Scholar
  238. Sari Y, Prieto AL, Barton SJ et al (2010) Ceftriaxone-induced up-regulation of cortical and striatal GLT1 in the R6/2 model of Huntington’s disease. J Biomed Sci 17:62PubMedCentralPubMedGoogle Scholar
  239. Sathasivam K, Lane A, Legleiter J et al (2010) Identical oligomeric and fibrillar structures captured from the brains of R6/2 and knock-in mouse models of Huntington’s disease. Hum Mol Genet 19:65–78PubMedCentralPubMedGoogle Scholar
  240. Sathasivam K, Neueder A, Gipson TA et al (2013) Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U S A 110:2366–2370PubMedCentralPubMedGoogle Scholar
  241. Sathyasaikumar KV, Stachowski EK, Amori L et al (2010) Dysfunctional kynurenine pathway metabolism in the R6/2 mouse model of Huntington’s disease. J Neurochem 113:1416–1425PubMedCentralPubMedGoogle Scholar
  242. Schiefer J, Sprunken A, Puls C et al (2004) The metabotropic glutamate receptor 5 antagonist MPEP and the mGluR2 agonist LY379268 modify disease progression in a transgenic mouse model of Huntington’s disease. Brain Res 1019:246–254PubMedGoogle Scholar
  243. Schmidt CJ, Chapin DS, Cianfrogna J et al (2008) Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther 325:681–690PubMedGoogle Scholar
  244. Schwarcz R, Bruno JP, Muchowski PJ et al (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13:465–477PubMedCentralPubMedGoogle Scholar
  245. Sebastian C, Satterstrom FK, Haigis MC et al (2012) From sirtuin biology to human diseases: an update. J Biol Chem 287:42444–42452PubMedCentralPubMedGoogle Scholar
  246. Seeger T (2003) Immunohistochemical localization of PDE10A in the rat brain. Brain Res 985:113–126PubMedGoogle Scholar
  247. Seong IS, Ivanova E, Lee JM et al (2005) HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet 14:2871–2880PubMedGoogle Scholar
  248. Shin BH, Lim Y, Oh HJ et al (2013) Pharmacological activation of Sirt1 Ameliorates Polyglutamine-induced toxicity through the regulation of autophagy. PLoS One 8:e64953PubMedCentralPubMedGoogle Scholar
  249. Shirasaki DI, Greiner ER, Al-Ramahi I et al (2012) Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron 75:41–57PubMedCentralPubMedGoogle Scholar
  250. Skaper SD, Di Marzo V (2012) Endocannabinoids in nervous system health and disease: the big picture in a nutshell. Philos Trans R Soc Lond B Biol Sci 367:3193–3200PubMedCentralPubMedGoogle Scholar
  251. Soldati C, Bithell A, Conforti P et al (2011) Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington’s disease. J Neurochem 116:415–425PubMedGoogle Scholar
  252. Sotty F, Montezinho LP, Steiniger-Brach B et al (2009) Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to d-amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons. J Neurochem 109:766–775PubMedGoogle Scholar
  253. Spina D (2008) PDE4 inhibitors: current status. Br J Pharmacol 155:308–315PubMedCentralPubMedGoogle Scholar
  254. Squitieri F, Landwehrmeyer B, Reilmann R et al (2013) One-year safety and tolerability profile of pridopidine in patients with Huntington disease. Neurology 80:1086–1094PubMedGoogle Scholar
  255. Steffan JS, Bodai L, Pallos J et al (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743PubMedGoogle Scholar
  256. Stiles DK, Zhang Z, Ge P et al (2012) Widespread suppression of huntingtin with convection-enhanced delivery of siRNA. Exp Neurol 233:463–471PubMedGoogle Scholar
  257. Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1:609–620PubMedGoogle Scholar
  258. Sugars KL (2003) Decreased cAMP Response Element-mediated Transcription: an early event in exon 1 and full-length cell models of Huntington’s disease that contributes to polyglutamine pathogenesis. J Biol Chem 279:4988–4999PubMedGoogle Scholar
  259. Switonski PM, Szlachcic WJ, Gabka A et al (2012) Mouse models of polyglutamine diseases in therapeutic approaches: review and data table. Part II. Mol Neurobiol 46:430–466Google Scholar
  260. Tabrizi SJ, Blamire AM, Manners DN et al (2003) Creatine therapy for Huntington’s disease: clinical and MRS findings in a 1-year pilot study. Neurology 61:141–142PubMedGoogle Scholar
  261. Tam S, Spiess C, Auyeung W et al (2009) The chaperonin TRiC blocks a huntingtin sequence element that promotes the conformational switch to aggregation. Nat Struct Mol Biol 16:1279–1285PubMedCentralPubMedGoogle Scholar
  262. Tang JK, Moro E, Lozano AM et al (2005) Firing rates of pallidal neurons are similar in Huntington’s and Parkinson’s disease patients. Exp Brain Res 166:230–236PubMedGoogle Scholar
  263. Tang B, Seredenina T, Coppola G et al (2011) Gene expression profiling of R6/2 transgenic mice with different CAG repeat lengths reveals genes associated with disease onset and progression in Huntington’s disease. Neurobiol Dis 42:459–467PubMedCentralPubMedGoogle Scholar
  264. Tarditi A, Camurri A, Varani K et al (2006) Early and transient alteration of adenosine A2A receptor signaling in a mouse model of Huntington disease. Neurobiol Dis 23:44–53PubMedGoogle Scholar
  265. Temel Y, Cao C, Vlamings R et al (2006) Motor and cognitive improvement by deep brain stimulation in a transgenic rat model of Huntington’s disease. Neurosci Lett 406:138–141PubMedGoogle Scholar
  266. Thakur AK, Jayaraman M, Mishra R et al (2009) Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism. Nat Struct Mol Biol 16:380–389PubMedCentralPubMedGoogle Scholar
  267. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983Google Scholar
  268. Thomas EA, Coppola G, Desplats PA et al (2008) The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington’s disease transgenic mice. Proc Natl Acad Sci U S A 105:15564–15569PubMedCentralPubMedGoogle Scholar
  269. Threlfell S, Sammut S, Menniti FS et al (2008) Inhibition of phosphodiesterase 10A increases the responsiveness of striatal projection neurons to cortical stimulation. J Pharmacol Exp Ther 328:785–795PubMedCentralPubMedGoogle Scholar
  270. Threlfell S, Sammut S, Menniti FS et al (2009) Inhibition of phosphodiesterase 10A increases the responsiveness of striatal projection neurons to cortical stimulation. J Pharmacol Exp Ther 328:785–795PubMedCentralPubMedGoogle Scholar
  271. Trevino RS, Lauckner JE, Sourigues Y et al (2012) Fibrillar structure and charge determine the interaction of polyglutamine protein aggregates with the cell surface. J Biol Chem 287:29722–29728PubMedCentralPubMedGoogle Scholar
  272. Tsao D, Thomsen HK, Chou J et al (2008) TrkB agonists ameliorate obesity and associated metabolic conditions in mice. Endocrinol 149:1038–1048Google Scholar
  273. van den Bogaard SJ, Dumas EM, Teeuwisse WM et al (2011) Exploratory 7-Tesla magnetic resonance spectroscopy in Huntington’s disease provides in vivo evidence for impaired energy metabolism. J Neurol 258:2230–2239PubMedCentralPubMedGoogle Scholar
  274. Van Laere K, Casteels C, Dhollander I et al (2010) Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. J Nucl Med 51:1413–1417PubMedGoogle Scholar
  275. Van Raamsdonk JM, Pearson J, Rogers DA et al (2005) Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease. Exp Neurol 196:266–272PubMedGoogle Scholar
  276. Vanevski F, Xu B (2013) Molecular and neural bases underlying roles of BDNF in the control of body weight. Front Neurosci 7:37PubMedCentralPubMedGoogle Scholar
  277. Vecsei L, Szalardy L, Fulop F et al (2013) Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov 12:64–82PubMedGoogle Scholar
  278. Velez-Lago FM, Thompson A, Oyama G et al (2013) Differential and better response to deep brain stimulation of chorea compared to dystonia in Huntington’s Disease. Stereotact Funct Neurosurg 91:129–133PubMedGoogle Scholar
  279. Venuto CS, McGarry A, Ma Q et al (2012) Pharmacologic approaches to the treatment of Huntington’s disease. Mov Disord 27:31–41PubMedGoogle Scholar
  280. Verbessem P, Lemiere J, Eijnde BO et al (2003) Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology 61:925–930PubMedGoogle Scholar
  281. Vlamings R, Benazzouz A, Chetrit J et al (2012) Metabolic and electrophysiological changes in the basal ganglia of transgenic Huntington’s disease rats. Neurobiol Dis 48:488–494PubMedGoogle Scholar
  282. Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384PubMedGoogle Scholar
  283. Wang ZM, Lashuel HA (2013) Discovery of a novel aggregation domain in the huntingtin protein: implications for the mechanisms of Htt aggregation and toxicity. Angew Chem Int Ed Engl 52:562–567PubMedGoogle Scholar
  284. Wang H, Peng MS, Chen Y et al (2007) Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J 408:193–201PubMedCentralPubMedGoogle Scholar
  285. Waterhouse EG, Xu B (2013) The skinny on brain-derived neurotrophic factor: evidence from animal models to GWAS. J Mol Med (Berl) 91(11):1241–1247. doi:10.1007/s00109-013-1071-8. Epub 2013 Jul 5 Google Scholar
  286. Weiss A, Trager U, Wild EJ et al (2012) Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression. J Clin Invest 122:3731–3736PubMedCentralPubMedGoogle Scholar
  287. Wen YD, Perissi V, Staszewski LM et al (2000) The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc Natl Acad Sci U S A 97:7202–7207PubMedCentralPubMedGoogle Scholar
  288. Wexler NS, Lorimer J, Porter J et al (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci U S A 101:3498–3503PubMedCentralPubMedGoogle Scholar
  289. Weydt P, Pineda VV, Torrence AE et al (2006) Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab 4:349–362PubMedGoogle Scholar
  290. Woda JM, Calzonetti T, Hilditch-Maguire P et al (2005) Inactivation of the Huntington’s disease gene (Hdh) impairs anterior streak formation and early patterning of the mouse embryo. BMC Dev Biol 5:17PubMedCentralPubMedGoogle Scholar
  291. Wolf RC, Thomann PA, Thomann AK et al (2013) Brain structure in preclinical Huntington’s disease: a multi-method approach. Neurodegener Dis 12(1):13–22Google Scholar
  292. Wright HH, Still CN, Abramson RK (1981) Huntington’s disease in black kindreds in South Carolina. Arch Neurol 38:412–414PubMedGoogle Scholar
  293. Xie Y, Hayden MR, Xu B (2010) BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci 30:14708–14718PubMedCentralPubMedGoogle Scholar
  294. Yamamoto A, Lucas JJ, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101:57–66PubMedGoogle Scholar
  295. Yang L, Calingasan NY, Wille EJ et al (2009) Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s diseases. J Neurochem 109:1427–1439PubMedCentralPubMedGoogle Scholar
  296. Zala D, Colin E, Rangone H et al (2008) Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet 17:3837–3846PubMedGoogle Scholar
  297. Zhang HT, Huang Y, Masood A et al (2008) Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacol 33:1611–1623Google Scholar
  298. Zhang SF, Hennessey T, Yang L et al (2011) Impaired brain creatine kinase activity in Huntington’s disease. Neurodegener Dis 8:194–201PubMedCentralPubMedGoogle Scholar
  299. Zhao W, Kruse JP, Tang Y et al (2008) Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451:587–590PubMedCentralPubMedGoogle Scholar
  300. Zuccato C, Valenza M, Cattaneo E (2010) Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 90:905–981PubMedGoogle Scholar
  301. Zuccato C, Marullo M, Vitali B et al (2011) Brain-derived neurotrophic factor in patients with Huntington’s disease. PLoS One 6:e22966PubMedCentralPubMedGoogle Scholar
  302. Zwilling D, Huang SY, Sathyasaikumar KV et al (2011) Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145:863–874PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.CHDI Management/CHDI Foundation Inc.Los AngelesUSA
  2. 2.CHDI Management/CHDI Foundation Inc.PrincetonUSA

Personalised recommendations