Murine Models of Huntington’s Disease for Evaluating Therapeutics

  • Natalia Kosior
  • Blair R. LeavittEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1780)


Huntington’s disease (HD) is an autosomal dominant progressive neurological disorder characterized by motor, cognitive, and psychiatric symptoms that typically present later on in life, although juvenile cases do exist. The identification of the disease-causing mutation, a CAG triplet repeat expansion in the HTT gene, in 1993 generated numerous investigations into the cellular and molecular pathways underlying the disorder. HD mouse models have played a prominent role in these studies, and the use of these mouse models of HD in the development and evaluation of novel therapeutic strategies is reviewed in this chapter. As new interventions and therapeutic approaches are evaluated and implemented, genetic mouse models will continue to be used with the hope of developing effective treatments for HD.


Huntington’s disease Mouse models Transgenic mice Neurodegeneration Polyglutamine disease Therapeutics 


  1. 1.
    Pringsheim T, Wiltshire K, Day L et al (2012) The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 27:1083–1091CrossRefPubMedGoogle Scholar
  2. 2.
    Rawlins MD, Wexler NS, Wexler AR et al (2016) The prevalence of Huntington’s disease. Neuroepidemiology 46(2):144–153CrossRefPubMedGoogle Scholar
  3. 3.
    Fisher ER, Hayden MR (2014) Multisource ascertainment of Huntington’s disease in Canada: prevalence and population at risk. Mov Disord 29(1):105–114CrossRefPubMedGoogle Scholar
  4. 4.
    Gusella JF, Wexler NS, Conneally PM et al (1983) A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 306(5940):234–238CrossRefPubMedGoogle Scholar
  5. 5.
    Anon et al (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell 72(6):971–983CrossRefGoogle Scholar
  6. 6.
    Gama Sosa MA, De Gasperi R, Elder GA (2012) Modeling human neurodegenerative diseases in transgenic systems. Hum Genet 131(4):535–563CrossRefPubMedGoogle Scholar
  7. 7.
    Wagner LA, Menalled L, Goumeniouk A et al (2008) Chapter 6: Huntington’s disease. In MacArthur, RA and Borsini F (eds.): Animal and Translational Models for CNS Drug Discovery: Neurological Disorders pp 207–266CrossRefGoogle Scholar
  8. 8.
    Harper B (2005) Huntington disease (online). Available from: CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Young AB, Shoulson I, Penney JB et al (1986) Huntington’s disease in Venezuela: neurologic features and functional decline. Neurology 36(2):244–249CrossRefPubMedGoogle Scholar
  10. 10.
    Nance MA, Myers RH (2001) Juvenile onset Huntington’s disease: clinical and research perspectives. Ment Retard Dev Disabil Res Rev 7(3):153–157CrossRefPubMedGoogle Scholar
  11. 11.
    Butters N, Wolfe J, Martone M et al (1985) Memory disorders associated with Huntington’s disease: verbal recall, verbal recognition and procedural memory. Neuropsychologia 23(6):729–743CrossRefPubMedGoogle Scholar
  12. 12.
    Zakzanis KK (1998) The subcortical dementia of Huntington’s disease. J Clin Exp Neuropsychol 20(4):565–578CrossRefPubMedGoogle Scholar
  13. 13.
    Anderson KE, Marder KS (2001) An overview of psychiatric symptoms in Huntington’s disease. Curr Psychiatry Rep 3(5):379–388CrossRefPubMedGoogle Scholar
  14. 14.
    Lovestone S, Hodgson S, Sham P et al (1996) Familial psychiatric presentation of Huntington’s disease. J Med Genet 33(2):128–131CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sanberg PR, Fibiger HC, Mark RF et al (1981) Body weight and dietary factors in Huntington’s disease patients compared with matched controls. Med J Aust 1(8):407–409PubMedGoogle Scholar
  16. 16.
    Morton AJ, Wood NI, Hastings MH et al (2005) Disintegration of the sleep-wake cycle and circadian timing in Huntington’s disease. J Neurosci 25(1):157–163CrossRefPubMedGoogle Scholar
  17. 17.
    Van Raamsdonk JM, Murphy Z, Selva DM et al (2007) Testicular degeneration in Huntington disease. Neurobiol Dis 26(3):512–520CrossRefPubMedGoogle Scholar
  18. 18.
    Sharp AH, Loev SJ, Schilling G et al (1995) Widespread expression of Huntington’s disease gene (IT15) protein product. Neuron 14(5):1065–1074CrossRefPubMedGoogle Scholar
  19. 19.
    Andrew SE, Goldberg YP, Kremer B et al (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 4(4):398–403CrossRefPubMedGoogle Scholar
  20. 20.
    Mahadevan M, Tsilfidis C, Sabourin L et al (1992) Mytonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 225(5049):1235–1255Google Scholar
  21. 21.
    Semaka A, Creighton S, Warby S, Hayden MR et al (2006) Predictive testing for Huntingons disease: interpretation and significance of intermediate alleles. Clin Genet 70(4):283–294CrossRefPubMedGoogle Scholar
  22. 22.
    Telenius H, Kremer HP, Theilmann J et al (1993) Molecular analysis of juvenile Huntington’s disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum Mol Genet 2(10):1535–1540CrossRefPubMedGoogle Scholar
  23. 23.
    Becanovic K, Norremolle A, Neal SJ et al (2015) A SNP in the HTT promoter alters NF-kB binding and is a bidirectional genetic modifier of Huntington’s disease. Nat Neurosci 18(6):807–816CrossRefPubMedGoogle Scholar
  24. 24.
    Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium (2015) Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell 162(3):516–526CrossRefGoogle Scholar
  25. 25.
    Vonsattel JP, DiFiglia M (1998) Huntington’s disease. J Neuropathol Exp Neurol 57(5):369–384CrossRefPubMedGoogle Scholar
  26. 26.
    Vonsattel JP, Myers RH, Stevens TJ et al (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44(6):559–577CrossRefPubMedGoogle Scholar
  27. 27.
    Davies SW, Turmaine M, Cozens BA et al (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90(3):537–548CrossRefPubMedGoogle Scholar
  28. 28.
    DiFiglia M, Sapp E, Chase KO et al (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neuritis in brain. Science 277(5334):1990–1993CrossRefPubMedGoogle Scholar
  29. 29.
    Coyle JT, Schwarcz R (1976) Lesion of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature 263(5574):244–246CrossRefPubMedGoogle Scholar
  30. 30.
    Beal MF, Ferrante RJ, Swartz KJ, Kowall NW (1991) Chronic quinolinic acid lesions in rats closely resemble Huntingtons-disease. J Neurosci 11(6):1649–1659CrossRefPubMedGoogle Scholar
  31. 31.
    Ludolph AC, He F, Spencer PS et al (1991) 3-Nitropropionic acid – exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci 18(4):492–498CrossRefPubMedGoogle Scholar
  32. 32.
    Mangiarini L, Sathasivam K, Seller M et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87(3):493–506CrossRefPubMedGoogle Scholar
  33. 33.
    Carter RJ, Lione LA, Humby T et al (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 19(8):3248–3257CrossRefPubMedGoogle Scholar
  34. 34.
    Li JY, Popovic N, Brundin P et al (2005) The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies. NeuroRx 2(3):447–464CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Schilling G, Becher MW, Sharp AH et al (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8(3):397–407CrossRefPubMedGoogle Scholar
  36. 36.
    Luthi-Carter R, Strand A, Peters NL et al (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9(9):1259–1271CrossRefPubMedGoogle Scholar
  37. 37.
    Andreassen OA, Dedeoglu A, Ferrante RJ et al (2001) Creatine increase survival and delays motor symptoms in transgenic animal model of Huntington’s disease. Neurobiol Dis 8(3):479–491CrossRefPubMedGoogle Scholar
  38. 38.
    Andreassen OA, Ferrante RJ, Huang HM et al (2001) Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington’s disease. Ann Neurol 50(1):112–117CrossRefPubMedGoogle Scholar
  39. 39.
    Andreassen OA, Ferrante RJ, Dedeoglu A, Beal MF et al (2001) Lipoic acid improves survival in transgenic mouse models of Huntington’s disease. Neuroreport 12(15):3371–3373CrossRefPubMedGoogle Scholar
  40. 40.
    Schilling G, Coonfield ML, Ross CA, Borchelt DR et al (2001) Coenzyme Q1 and remacemide hydrochloride ameloriate motor deficits in Huntington’s disease transgenic mouse model. Neurosci Lett 315(3):149–153CrossRefPubMedGoogle Scholar
  41. 41.
    Slow EJ, Graham RK, Osmand AP et al (2005) Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc Natl Acad Sci U S A 102(32):11402–11407CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Reddy PH, Charles V, Williams M et al (1999) Transgenic mice expressing mutated full-length HD cDNA: a paradigm for locomotor changes and selective neuronal loss in Huntington’s disease. Philos Trans R Soc Lond Ser B Biol Sci 354(1386):1035–1045CrossRefGoogle Scholar
  43. 43.
    Tanaka Y, Igarashi S, Nakamura M et al (2006) Progressive phenotype and nuclear accumulation of an amino-terminal cleavage fragment in a transgenic mouse model with inducible expression of full-length mutant huntingtin. Neurobiol Dis 21(2):381–391CrossRefPubMedGoogle Scholar
  44. 44.
    Hodgson JG, Agopyan N, Gutekunst CA et al (1999) A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23(1):181–192CrossRefPubMedGoogle Scholar
  45. 45.
    Slow EJ, van Raamsdonk J, Rogers D et al (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12(13):1555–1567CrossRefPubMedGoogle Scholar
  46. 46.
    Van Raamsdonk JM, Pearson J, Slow EJ et al (2005) Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington’s disease. J Neurosci 25(16):4169–4180. CrossRefPubMedGoogle Scholar
  47. 47.
    Gray M, Shirasaki DI, Cepeda C et al (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28(24):6182–6195. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Barnes GT, Duyao MP, Ambrose CM et al (1994) Mouse Huntingtons-disease gene homology (Hdh). Somat Cell Mol Genet 20(2):87–94CrossRefPubMedGoogle Scholar
  49. 49.
    White JK, Auerbach W, Duyao MP et al (1997) Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat Genet 17(4):404–410CrossRefPubMedGoogle Scholar
  50. 50.
    Levine MS, Klapstein GJ, Koppel A et al (1999) Enhanced sensitivity to N-methyl-d-aspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J Neurosci Res 58(4):515–532CrossRefPubMedGoogle Scholar
  51. 51.
    Lin CH, Tallaksen-Greene S, Chien WM et al (2001) Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 10(2):137–144CrossRefPubMedGoogle Scholar
  52. 52.
    Shelbourne PF, Killeen N, Hevner RF et al (1999) A Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum Mol Genet 8(5):763–774CrossRefPubMedGoogle Scholar
  53. 53.
    Wheeler VC, White JK, Gutekunst CA et al (2000) Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in Hdh(Q92) and Hdh(Q111) knock-in mice. Hum Mol Genet 9(4):503–513CrossRefPubMedGoogle Scholar
  54. 54.
    Menalled LB, Sison JD, Dragatsis I et al (2003) Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. J Comp Neurol 465(1):11–26CrossRefPubMedGoogle Scholar
  55. 55.
    Heng MY, Duong DK, Albin RL et al (2010) Early autophagic response in a novel knock-in model of Huntington disease. Hum Mol Genet 19(19):3702–3720. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Heng MY, Detloff PJ, Paulson HL, Albin RL (2010) Early alterations of autophagy in Huntington disease-like mice. Autophagy 6(8):1206–1208CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Squitieri F, Gellera C, Cannella M et al (2003) Homozygosity for CAG mutation in Huntington disease is associated with more severe clinical course. Brain 126:946–955CrossRefPubMedGoogle Scholar
  58. 58.
    Menalled LB, Kudwa AE, Miller S et al (2012) Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington’s disease: zQ175. PLoS One 12(7):e49838. [Epub 2012 Dec 20]CrossRefGoogle Scholar
  59. 59.
    Southwell AL, Smith-Dijak A, Kay C et al (2016) An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes. Hum Mol Genet. Jul 4. pii: ddw212 [Epub ahead of print]Google Scholar
  60. 60.
    Gaveriaux-Ruff C, Kieffer B (2007) Conditional gene targeting in the mouse nervous system: insights into brain function and diseases. Pharmacol Ther 113:619–634CrossRefPubMedGoogle Scholar
  61. 61.
    Mazarei G, Leavitt BR (2014) Murine models of HD. In: Movement disorders: genetics and models, 2nd edn. Elsevier, Amsterdam, pp 533–546Google Scholar
  62. 62.
    Yamamoto A, Lucas JJ, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101(1):57–66CrossRefPubMedGoogle Scholar
  63. 63.
    Furth PA, St Onge L, Boger H et al (1994) Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci U S A 91(20):9302–9306CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Díaz-Hernández M, Torres-Peraza J, Salvatori-Abarca A et al (2005) Full motor recovery despite striatal neuron loss and formation of irreversible amyloid-like inclusions in a conditional mouse model of Huntington’s disease. J Neurosci 25(42):9773–9781CrossRefPubMedGoogle Scholar
  65. 65.
    Bradford J, Shin JY, Roberts M et al (2009) Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci U S A 106(52):22480–22485. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Bradford J, Shin JY, Roberts M et al (2010) Mutant huntingtin in glial cells exacerbates neurological symptoms of Huntington disease mice. J Biol Chem 285(14):10653–10661CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    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(15):3053–3067CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Molero AE, Arteaga-Bracho EE, Chen CH et al (2016) Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease. Proc Natl Acad Sci U S A 113(20):5736–5741CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Southwell AL, Warby SC, Carroll JB et al (2013) A fully humanized transgenic mouse model of Huntington disease. Hum Mol Genet 22(1):18–34CrossRefPubMedGoogle Scholar
  70. 70.
    Kolodziejczyk K, Parsons MP, Southwell AL et al (2014) Striatal synaptic dysfunction and hippocampal plasticity deficits in the Hu97/18 mouse model of Huntington disease. PLoS One 9(4):e94562. eCollection 2014CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Menalled L, Lutz C, Ramboz S et al (2014) A field guide to working with mouse models of Huntington’s disease.
  72. 72.
    Weller A, Leguisamo AC, Towns L et al (2003) Maternal effects in infant and adult phenotypes of 5HT1A and 5HT1B receptor knockout mice. Dev Psychobiol 42:194–205CrossRefPubMedGoogle Scholar
  73. 73.
    Brunner D, Buhot MC, Hen R, Hofer M (1999) Anxiety, motor activation and maternal infant interactions in 5HT1B knockout mice. Behav Neurosci 113(3):587–601CrossRefPubMedGoogle Scholar
  74. 74.
    Hockly E, Cordery PM, Woodman B et al (2002) Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann Neurol 51(2):235–242CrossRefPubMedGoogle Scholar
  75. 75.
    Farley SJ, McKay BM, Disterhoft JF, Weiss C (2011) Reevaluating hippocampus dependent learning in FVB/N mice. Behav Neurosci 125(6):871–878CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Schauwecker PE (2005) Susceptibility to excitotoxic and metabolic striatal neurodegeneration in the mouse is genotype dependent. Brain Res 1040:112–120CrossRefPubMedGoogle Scholar
  77. 77.
    Van Raamsdonk JM, Metzler M, Slow E et al (2007) Phenotypic abnormalities in the YAC128 mouse model of Huntington’s disease are penetrant on multiple genetic backgrounds and modulated by strain. Neurobiol Dis 26:189–200CrossRefPubMedGoogle Scholar
  78. 78.
    Orvoen S, Pla P, Gardier AM, Saudou F, David DJ (2012) Huntington’s disease knock-in male mice show specific anxiety-like behavior and altered neuronal maturation. Neurosci Lett 507:127–132CrossRefPubMedGoogle Scholar
  79. 79.
    Aziz NA, van der Burg JM, Landwehrmeyer GB, Brunding P, Stijnen T, EHDI Study Group, Roos RA (2008) Weight loss in Huntington’s disease increases with higher CAG repeat number. Neurology 71(19):1506–1513. CrossRefPubMedGoogle Scholar
  80. 80.
    Hamm RJ, Pike BR, O’Dell DM, Lyeth BG, Jenkins LW (1994) The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma 11(2):187–196CrossRefPubMedGoogle Scholar
  81. 81.
    Pallier PN, Drew CK, Morton AJ (2009) The detection and measurement of locomotor deficits in a transgenic mouse model of Huntington’s disease are task-and-protocol dependent: influence of non-motor factors on locomotor function. Brain Res Bull 78:347–355CrossRefPubMedGoogle Scholar
  82. 82.
    Hockly E (2003) Standardization and statistical approaches to therapeutic trials in the R6/2 mouse. Brain Res Bull 61:469–479CrossRefPubMedGoogle Scholar
  83. 83.
    Hickey MA, Gallant K, Gross GG, Levine MS, Chesselet MF (2005) Early behavioral deficits in R6/2 mice suitable for use in preclinical drug testing. Neurobiol Dis 20(1):1–11CrossRefPubMedGoogle Scholar
  84. 84.
    Craufurd D, Snowden J (2002) Neuropsychological and neuropsychiatric aspects of Huntington’s disease. In: Bates G, Harper PS, Jones L (eds) Huntington's disease, 3rd edn. Oxford University Press, Oxford, pp 62–94Google Scholar
  85. 85.
    Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11(1):47–60CrossRefPubMedGoogle Scholar
  86. 86.
    Block F, Kunkel M, Schwarz M (1993) Quinolinic acid lesion of the striatum induces impairment in spatial learning and motor performance in rats. Neurosci Lett 149(2):126–128CrossRefPubMedGoogle Scholar
  87. 87.
    Abada YS, Schreiber R, Ellebroek B (2013) Motor, emotional and cognitive deficits in adult BACHD mice: a model for Huntington’s disease. Behav Brain Res 238:243–251CrossRefPubMedGoogle Scholar
  88. 88.
    File SE, Mahal A, Mangiarini L, Bates GP (1998) Striking changes in anxiety in Huntington’s disease transgenic mice. Brain Res 805:234–240CrossRefPubMedGoogle Scholar
  89. 89.
    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 19:264–275CrossRefPubMedGoogle Scholar
  90. 90.
    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 19:65–78CrossRefPubMedGoogle Scholar
  91. 91.
    Weiss WF, Hodgdon TK, Kaler EW, Lenhoff AM, Roberts CJ et al (2007) Nonnative protein polymers: structure, morphology, and relation to nucleation and growth. Biophys J 93:4392–4403CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Bayram-Weston Z, Jones L, Dunnet SB, Brooks SP (2016) Comparison of mHTT antibodies in Huntington’s disease mouse models reveal specific binding profiles and steady state ubiquitin levels with disease development. PLoS One 11(15):e0155834. CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Labadorf A, Hoss AG, Lagomarsino V et al (2015) RNA sequence analysis of human Huntington disease brain reveals an extensive increase in inflammatory and developmental gene expression. PLoS One 11(7):e0160295. CrossRefGoogle Scholar
  94. 94.
    Miller JRC, Lo KK, Andre R et al (2016) RNA-Seq of Huntington’s disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation. Hum Mol Genet 25(14):2893–2904. CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Carroll JB, Lerch JP, Franicosi S et al (2011) Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease. Neurobiol Dis 43:257–265CrossRefPubMedGoogle Scholar
  96. 96.
    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:e50717CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Hickey MA, Kosmalska A, Enayati J et al (2008) Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington’s disease mice. Neuroscience 157:280–295CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Brunner D, Balci F, Ludvig EA (2012) Comparative psychology and the grand challenge of drug discovery in psychiatry and neurodegeneration. Behav Process 89:187–195CrossRefGoogle Scholar
  99. 99.
    Menalled LM, Brunner D (2014) Animal models of Huntington’s disease for translation to the clinic: best practices. Mov Disord 15(29):1375–1390. CrossRefGoogle Scholar
  100. 100.
    Wild E, Tabrizi SJ (2014) Targets for future clinical trials in Huntington’s disease: what’s in the pipeline? Mov Disord 29(11):1434–1445. CrossRefPubMedGoogle Scholar
  101. 101.
    Pavon-Agustin C, Mielcarek M, Canut-Garriga M, Isalan M (2016) Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice. Mol Neurodegener 11(1):64. CrossRefGoogle Scholar
  102. 102.
    Garriga-Canut M, Agustin-Pavon C, Herrmann F et al (2012) Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci U S A 109(45):E3136–E3145. CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Dalston NA, Gonzalez-Barriga A, Kourkouta E et al (2017) The expanded CAG repeat in the huntingtin gene as a target for therapeutic RNA modulation throughout the HD mouse brain. PLoS One 12(2):e0171127. CrossRefGoogle Scholar
  104. 104.
    Rue L, Coronel-Banez M, Muncunil-Creus J et al (2016) Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels. J Clin Invest 126(11):4319–4330. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Monteys AM, Ebanks SA, Kesier MS, Davidson BL (2017) CRISPR/Cas9 editing of the mutant huntingtin allele in vitro and in vivo. Mol Ther 25(1):12–23. CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Kratter IH, Zahed H, Lau A et al (2016) Serine 421 regulates huntingtin toxicity and clearance in mice. J Clin Invest 126(9):3585–3597. CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Ochaba J, Monteys AM, O’Rourke JG et al (2016) PIAS1 regulates mutant huntingtin accumulation and Huntington’s disease-associated phenotypes in vivo. Neuron 90(3):507–520. CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Lee JH, Tecedor L, Chen YH et al (2015) Reinstating aberrant mTORC1 activity in Huntington’s disease mice improves disease phenotype. Neuron 85(2):303–315. CrossRefPubMedGoogle Scholar
  109. 109.
    Chopra V, Quinti L, Khanna P et al (2016) LBH589, a hydroxamic acid-derived HDAC inhibitor is neuroprotective in mouse models of Huntington’s disease. J Huntingtons Dis 5(4):347–355CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Squitieri F, Di Pardo A, Favellato M, Amico E, Maglione V, Frati L (2015) Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model. J Cell Mol Med 19(11):2540–2548. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Geva M, Kusko R, Soares H et al (2016) Pridopidine activates neuroprotective pathways impaired in Huntington’s disease. Hum Mol Genet 25(18):3975–3987. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, Bezprozvanny I (2017) The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington’s disease. Neurobiol Dis 97(Pt A):46–59. CrossRefPubMedGoogle Scholar
  113. 113.
    Corey-Bloom J, Jia H, Aikin AM, Thomas EA (2014) Disease modifying potential of glatiramer acetate in Huntington’s disease. J Huntingtons Dis 3(3):311–316. CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Imamura T, Fujita K, Tagawa K et al (2016) Identification of hepta-histidine as a candidate drug for Huntington’s disease by in silico-in vitro-in vivo-integrated screens of chemical libraries. Sci Rep 6:33861. CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Garcia-Miralles M, Hong X, Tan JL et al (2016) Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioral improvements in the YAC128 model of Huntington’s disease. Sci Rep 6:31652. CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Valdeolivas S, Navarrete C, Cantarero I, Bellido ML, Munoz E, Sagredo O (2015) Neuroprotective properties of cannabigerol in Huntington’s disease: studies in R6/2 mice and 3-nitropropionate-lesioned mice. Neurotherapeutics 12(1):185–199. CrossRefPubMedGoogle Scholar
  117. 117.
    Diaz-Alonso J, Paraiso-Luna J, Navarrete C et al (2016) VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington’s disease. Sci Rep 6:29789. CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Wright DJ, Renoir T, Smith ZM et al (2015) N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington’s disease. Transl Psychiatry 5:e492. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre for Molecular Medicine and Therapeutics, and Department of Medical Genetics, BC Children’s Hospital Research InstituteUniversity of British ColumbiaVancouverCanada

Personalised recommendations