, Volume 2, Issue 3, pp 447–464 | Cite as

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies



Huntington’s disease (HD) is a genetic neurodegenerative disorder. Since identification of the disease-causing gene in 1993, a number of genetically modified animal models of HD have been generated. The first transgenic mouse models, R6/1 and R6/2 lines, were established 8 years ago. The R6/2 mice have been the best characterized and the most widely used model to study pathogenesis of HD and therapeutic interventions. In the present review, we especially focus on the characteristics of R6 transgenic mouse models and, in greater detail, describe the different therapeutic strategies that have been tested in these mice. We also, at the end, critically assess the relevance of the HD mouse models compared with the human disease and discuss how they can be best used in the future.

Key Words

Huntington’s disease therapy transgenic mice R6/2 neurodegenerative diseases 


  1. 1.
    Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87: 493–506, 1996.PubMedGoogle Scholar
  2. 2.
    Menalled LB, Chesselet MF. Mouse models of Huntington’s disease. Trends Pharmacol Sci 23: 32–39, 2002.PubMedGoogle Scholar
  3. 3.
    Group HsDCR. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72: 971–983, 1993.Google Scholar
  4. 4.
    Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol 57: 369–384, 1998.PubMedGoogle Scholar
  5. 5.
    Kiemer HP, Roos RA, Dingjan GM, Bots GT, Bruyn GW, Hofman MA. The hypothalamic lateral tuberal nucleus and the characteristics of neuronal loss in Huntington’s disease. Neurosci Lett 132: 101–104, 1991.Google Scholar
  6. 6.
    Kiemer HP, Roos RA, Dingjan G, Marani E, Bots GT. Atrophy of the hypothalamic lateral tuberal nucleus in Huntington’s disease. J Neuropathol Exp Neurol 49: 371–382, 1990.Google Scholar
  7. 7.
    Qin ZH, Wang Y, Sapp E, Cuiffo B, Wanker E, Hayden MR, et al. Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J Neurosci 24: 269–281, 2004.PubMedGoogle Scholar
  8. 8.
    Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington’s disease. EMBO Rep 5: 958–963, 2004.PubMedGoogle Scholar
  9. 9.
    Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805–810, 2004.PubMedGoogle Scholar
  10. 10.
    Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95: 55–66, 1998.PubMedGoogle Scholar
  11. 11.
    Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, et al. A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23: 181–192, 1999.PubMedGoogle Scholar
  12. 12.
    Hockly E, Woodman B, Mahal A, Lewis CM, Bates G. Standardization and statistical approaches to therapeutic trials in the R6/2 mouse. Brain Res Bull 61: 469–479, 2003.PubMedGoogle Scholar
  13. 13.
    Rubinsztein DC. Lessons from animal models of Huntington’s disease. Trends Genet 18: 202–209, 2002.PubMedGoogle Scholar
  14. 14.
    Luesse HG, Schiefer J, Spruenken A, Puls C, Block F, Kosinski CM. Evaluation of R6/2 HD transgenic mice for therapeutic studies in Huntington’s disease: behavioral testing and impact of diabetes mellitus. Behav Brain Res 126: 185–195, 2001.PubMedGoogle Scholar
  15. 15.
    Lione LA, Carter RJ, Hunt MJ, Bates GP, Morton AJ, Dunnett SB. Selective discrimination learning impairments in mice expressing the human Huntington’s disease mutation. J Neurosci 19:10428–10437, 1999.Google Scholar
  16. 16.
    Murphy KP, Carter RJ, Lione LA, Mangiarini L, Mahal A, Bates GP, et al. Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington’s disease mutation. J Neurosci 20: 5115–5123, 2000.PubMedGoogle Scholar
  17. 17.
    Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, Bates GP, et al. Characterization of progressive motor deficits in mice transgenic for the human Huntington’s disease mutation. J Neurosci 19: 3248–3257, 1999.PubMedGoogle Scholar
  18. 18.
    Hansson O, Guatteo E, Mercuri NB, Bernardi G, Li XJ, Castilho RF, et al. Resistance to NMDA toxicity correlates with appearance of nuclear inclusions, behavioural deficits and changes in calcium homeostasis in mice transgenic for exon 1 of the huntington gene. Eur J Neurosci 14: 1492–1504, 2001.PubMedGoogle Scholar
  19. 19.
    Sathasivam K, Hobbs C, Turmaine M, Mangiarini L, Mahal A, Bertaux F, et al. Formation of polyglutamine inclusions in non-CNS tissue. Hum Mol Genet 8: 813–822, 1999.PubMedGoogle Scholar
  20. 20.
    Hurlbert MS, Zhou W, Wasmeier C, Kaddis FG, Hutton JC, Freed CR. Mice transgenic for an expanded CAG repeat in the Huntington’s disease gene develop diabetes. Diabetes 48: 649–651, 1999.PubMedGoogle Scholar
  21. 21.
    Bjorkqvist M, Fex M, Renström E, Wierup N, Petersen A, Gil J, et al. The R6/2 transgenic mouse model of Huntington’s disease develops diabetes due to deficient β-cell mass and altered exocytosis. Hum Mol Genet 14: 565–574, 2005.PubMedGoogle Scholar
  22. 22.
    Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90: 537–548, 1997.PubMedGoogle Scholar
  23. 23.
    Hansson O, Petersen A, Leist M, Nicotera P, Castilho RF, Brundin P. Transgenic mice expressing a Huntington’s disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. Proc Natl Acad Sci USA 96: 8727–8732, 1999.PubMedGoogle Scholar
  24. 24.
    Turmaine M, Raza A, Mahal A, Mangiarini L, Bates GP, Davies SW. Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington’s disease. Proc Natl Acad Sci USA 97: 8093–8097, 2000.PubMedGoogle Scholar
  25. 25.
    Iannicola C, Moreno S, Oliverio S, Nardacci R, Ciofi-Luzzatto A, Piacentini M. Early alterations in gene expression and cell morphology in a mouse model of Huntington’ s disease. J Neurochem 75: 830–839, 2000.PubMedGoogle Scholar
  26. 26.
    Petersen A, Gil J, Maat-Schieman ML, Bjorkqvist M, Tanila H, Araujo IM, et al. Orexin loss in Huntington’s disease. Hum Mol Genet 14: 39–47, 2005.PubMedGoogle Scholar
  27. 27.
    Deleted in proof.Google Scholar
  28. 28.
    Klapstein GJ, Fisher RS, Zanjani H, Cepeda C, Jokel ES, Chesselet MF, et al. Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington’s disease transgenic mice. J Neurophysiol 86: 2667–2677, 2001.PubMedGoogle Scholar
  29. 29.
    Petersen A, Puschban Z, Lotharius J, NicNiocaill B, Wiekop P, O’Connor WT, et al. Evidence for dysfunction of the nigrostriatal pathway in the R6/1 line of transgenic Huntington’ s disease mice. Neurobiol Dis 11: 134–146, 2002.PubMedGoogle Scholar
  30. 30.
    Morton AJ, Lagan MA, Skepper JN, Dunnett SB. Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington’s disease mutation. J Neurocytol 29: 679–702, 2000.PubMedGoogle Scholar
  31. 31.
    Meade CA, Deng YP, Fusco FR, Del Mar N, Hersch S, Goldowitz D, et al. Cellular localization and development of neuronal intranuclear inclusions in striatal and cortical neurons in R6/2 transgenic mice. J Comp Neurol 449: 241–269, 2002.PubMedGoogle Scholar
  32. 32.
    Kosinski CM, Cha JH, Young AB, Mangiarini L, Bates G, Schiefer J, et al. Intranuclear inclusions in subtypes of striatal neurons in Huntington’s disease transgenic mice. Neuroreport 10: 3891–3896, 1999.PubMedGoogle Scholar
  33. 33.
    Jana NR, Zemskov EA, Wang G, Nukina N. Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet 10: 1049–1059, 2001.PubMedGoogle Scholar
  34. 34.
    Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, et al. Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9: 1259–1271, 2000.PubMedGoogle Scholar
  35. 35.
    Luthi-Carter R, Hanson SA, Strand AD, Bergstrom DA, Chun W, Peters NL, et al. Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum Mol Genet 11: 1911–1926, 2002.PubMedGoogle Scholar
  36. 36.
    Bogdanov MB, Andreassen OA, Dedeoglu A, Ferrante RJ, Beal MF. Increased oxidative damage to DNA in a transgenic mouse model of Huntington’s disease. J Neurochem 79: 1246–1249, 2001.PubMedGoogle Scholar
  37. 37.
    Santamaria A, Perez-Severiano F, Rodriguez-Martinez E, Maldonado PD, Pedraza-Chaverri J, Rios C, et al. Comparative analysis of Superoxide dismutase activity between acute pharmacological models and a transgenic mouse model of Huntington’s disease. Neurochem Res 26: 419–424, 2001.PubMedGoogle Scholar
  38. 38.
    Tabrizi SJ, Workman J, Hart PE, Mangiarini L, Mahal A, Bates G, et al. Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann Neurol 47: 80–86, 2000.PubMedGoogle Scholar
  39. 39.
    Perez-Severiano F, Escalante B, Vergara P, Rios C, Segovia J. Age-dependent changes in nitric oxide synthase activity and protein expression in striata of mice transgenic for the Huntington’s disease mutation. Brain Res 951:36–42, 2002.Google Scholar
  40. 40.
    Deckel AW, Gordinier A, Nuttal D, Tang V, Kuwada C, Freitas R, et al. Reduced activity and protein expression of NOS in R6/2 HD transgenic mice: effects of L-NAME on symptom progression. Brain Res 919: 70–81, 2001.PubMedGoogle Scholar
  41. 41.
    Deckel AW, Tang V, Nuttal D, Gary K, Elder R. Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington’s disease transgenic mice. Brain Res 939: 76–86, 2002.PubMedGoogle Scholar
  42. 42.
    Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P, et al. Expanded CAG repeats in exon 1 of the Huntington’s disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet 10: 1243–1254, 2001.PubMedGoogle Scholar
  43. 43.
    Levine MS, Klapstein GJ, Koppel A, Gruen E, Cepeda C, Vargas ME, et al. Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J Neurosci Res 58: 515–532, 1999.PubMedGoogle Scholar
  44. 44.
    Cepeda C, Hurst RS, Calvert CR, Hemandez-Echeagaray E, Nguyen OK, Jocoy E, et al. Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease. J Neurosci 23: 961–969, 2003.PubMedGoogle Scholar
  45. 45.
    Nicniocaill B, Haraldsson B, Hansson O, O’Connor WT, Brundin P. Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic mice. Eur J Neurosci 13: 206–210, 2001.PubMedGoogle Scholar
  46. 46.
    Lievens JC, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L, et al. Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 8: 807–821, 2001.PubMedGoogle Scholar
  47. 47.
    Behrens PF, Franz P, Woodman B, Lindenberg KS, Landwehrmeyer GB. Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation. Brain 125: 1908–1922, 2002.PubMedGoogle Scholar
  48. 48.
    Hickey MA, Reynolds GP, Morton AJ. The role of dopamine in motor symptoms in the R6/2 transgenic mouse model of Huntington’s disease. J Neurochem 81: 46–59, 2002.PubMedGoogle Scholar
  49. 49.
    Reynolds GP, Dalton CF, Tillery CL, Mangiarini L, Davies SW, Bates GP. Brain neurotransmitter deficits in mice transgenic for the Huntington’s disease mutation. J Neurochem 72: 1773–1776, 1999.PubMedGoogle Scholar
  50. 50.
    Ariano MA, Aronin N, Difiglia M, Tagle DA, Sibley DR, Leavitt BR, et al. Striatal neurochemical changes in transgenic models of Huntington’s disease. J Neurosci Res 68: 716–729, 2002.PubMedGoogle Scholar
  51. 51.
    Yohrling IG, Jiang GC, DeJohn MM, Robertson DJ, Vrana KE, Cha JH. Inhibition of tryptophan hydroxylase activity and decreased 5-HT1A receptor binding in a mouse model of Huntington’s disease. J Neurochem 82: 1416–1423, 2002.Google Scholar
  52. 52.
    Morton AJ, Faull RL, Edwardson JM. Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease. Brain Res Bull 56: 111–117, 2001.PubMedGoogle Scholar
  53. 53.
    Morton AJ, Edwardson JM. Progressive depletion of complexin II in a transgenic mouse model of Huntington’s disease. J Neurochem 76: 166–172, 2001.PubMedGoogle Scholar
  54. 54.
    Lievens JC, Woodman B, Mahal A, Bates GP. Abnormal phosphorylation of synapsin I predicts a neuronal transmission impairment in the R6/2 Huntington’s disease transgenic mice. Mol Cell Neurosci 20: 638–648, 2002.PubMedGoogle Scholar
  55. 55.
    Modregger J, DiProspero NA, Charles V, Tagle DA, Plomann M. PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington’s disease brains. Hum Mol Genet 11: 2547–2558, 2002.PubMedGoogle Scholar
  56. 56.
    Smith R, Petersen A, Bates G, Brundin P, Li JY. Depletion of rabphilin 3A in a transgenic mouse model (R6/1) of Huntington’s Disease, a possible culprit in synaptic dysfunction. Neurobiol Dis, in press.Google Scholar
  57. 57.
    Cha JH, Frey AS, Aisdorf SA, Kerner JA, Kosinski CM, Mangiarini L, et al. Altered neurotransmitter receptor expression in transgenic mouse models of Huntington’s disease. Philos Trans R Soc Lond B Biol Sci 354: 981–989, 1999.PubMedGoogle Scholar
  58. 58.
    Bibb JA, Yan Z, Svenningsson P, Snyder GL, Pieribone VA, Horiuchi A, et al. Severe deficiencies in dopamine signaling in presymptomatic Huntington’s disease mice. Proc Natl Acad Sci USA 97: 6809–6814, 2000.PubMedGoogle Scholar
  59. 59.
    van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ. Delaying the onset of Huntington’s in mice. Nature 404: 721–722, 2000.PubMedGoogle Scholar
  60. 60.
    Zucker B, Luthi-Carter R, Kama JA, Dunah AW, Stem EA, Fox JH, et al. Transcriptional dysregulation in striatal projection- and intemeurons in a mouse model of Huntington’s disease: neuronal selectivity and potential neuroprotective role of HAP1. Hum Mol Genet 14: 179–189, 2005.PubMedGoogle Scholar
  61. 61.
    Petersen A, Hansson O, Puschban Z, Sapp E, Romero N, Castilho RF, et al. Mice transgenic for exon 1 of the Huntington’s disease gene display reduced striatal sensitivity to neurotoxicity induced by dopamine and 6-hydroxydopamine. Eur J Neurosci 14: 1425–1435, 2001.PubMedGoogle Scholar
  62. 62.
    Hansson O, Castilho RF, Korhonen L, Lindholm D, Bates GP, Brundin P. Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington’s disease is dependent on age and CAG repeat length. J Neurochem 78: 694–703, 2001.PubMedGoogle Scholar
  63. 63.
    Schiefer J, Alberty A, Dose T, Oliva S, Noth J, Kosinski CM. Huntington’s disease transgenic mice are resistant to global cerebral ischemia. Neurosci Lett 334: 99–102, 2002.PubMedGoogle Scholar
  64. 64.
    Morton AJ, Leavens W. Mice transgenic for the human Huntington’s disease mutation have reduced sensitivity to kainic acid toxicity. Brain Res Bull 52: 51–59, 2000.PubMedGoogle Scholar
  65. 65.
    Hickey MA, Morton AJ. Mice transgenic for the Huntington’s disease mutation are resistant to chronic 3-nitropropionic acid-induced striatal toxicity. J Neurochem 75: 2163–2171, 2000.PubMedGoogle Scholar
  66. 66.
    Li JY, Plomann M, Brundin P. Huntington’s disease: a synaptopathy? Trends Mol Med 9: 414–420, 2003.PubMedGoogle Scholar
  67. 67.
    Rubinsztein DC, Carmichael J. Huntington’s disease: molecular basis of neurodegeneration. Expert Rev Mol Med 5: 1–21, 2003.PubMedGoogle Scholar
  68. 68.
    Sugars KL, Rubinsztein DC. Transcriptional abnormalities in Huntington disease. Trends Genet 19: 233–238, 2003.PubMedGoogle Scholar
  69. 69.
    Ciechanover A, Brundin P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40: 427–446, 2003.PubMedGoogle Scholar
  70. 70.
    Beal MF. Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 23: 298–304, 2000.PubMedGoogle Scholar
  71. 71.
    Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitinproteasome system by protein aggregation. Science 292: 1552–1555, 2001.PubMedGoogle Scholar
  72. 72.
    Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19: 148–154, 1998.PubMedGoogle Scholar
  73. 73.
    Fink AL. Chaperone-mediated protein folding. Physiol Rev 79: 425–449, 1999.PubMedGoogle Scholar
  74. 74.
    Haiti FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295: 1852–1858, 2002.Google Scholar
  75. 75.
    Hay DG, Sathasivam K, Tobaben S, Stahl B, Marber M, Mestril R, et al. Progressive decrease in chaperone protein levels in a mouse model of Huntington’s disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet 13: 1389–1405, 2004.PubMedGoogle Scholar
  76. 76.
    Hansson O, Nylandsted J, Castilho RF, Leist M, Jaattela M, Brundin P. Overexpression of heat shock protein 70 in R6/2 Huntington’s disease mice has only modest effects on disease progression. Brain Res 970: 47–57, 2003.PubMedGoogle Scholar
  77. 77.
    Sittler A, Lurz R, Lueder G, Priller J, Hayer-Hartl MK, Haiti FU, et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Hum Mol Genet 10: 1307–1315, 2001.PubMedGoogle Scholar
  78. 78.
    Smith DL, Portier R, Woodman B, Hockly E, Mahal A, Klunk WE, et al. Inhibition of polyglutamine aggregation in R6/2 HD brain slices-complex dose-response profiles. Neurobiol Dis 8: 1017–1026, 2001.PubMedGoogle Scholar
  79. 79.
    Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R, Schugardt N, et al. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington’s disease therapy. Proc Natl Acad Sci USA 97: 6739–6744, 2000.PubMedGoogle Scholar
  80. 80.
    Sanchez I, Mahlke C, Yuan J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421: 373–379, 2003.PubMedGoogle Scholar
  81. 81.
    Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101: 57–66, 2000.PubMedGoogle Scholar
  82. 82.
    Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S, et al. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington’s disease by using an automated filter retardation assay. Proc Nail Acad Sci USA 99 [Suppl 4]: 16400–16406, 2002.Google Scholar
  83. 83.
    Schiefer J, Landwehrmeyer GB, Luesse HG, Sprunken A, Puls C, Milkereit A, et al. Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington’s disease. Mov Disord 17: 748–757, 2002.PubMedGoogle Scholar
  84. 84.
    Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10: 148–154, 2004.PubMedGoogle Scholar
  85. 85.
    Kegel KB, Meloni AR, Yi Y, Kim YJ, Doyle E, Cuiffo BG, et al. Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription. J Biol Chem 277: 7466–7476, 2002.PubMedGoogle Scholar
  86. 86.
    Martindale D, Hackam A, Wieczorek A, Ellerby L, Wellington C, McCutcheon K, et al. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet 18: 150–154, 1998.PubMedGoogle Scholar
  87. 87.
    Preisinger E, Jordan BM, Kazantsev A, Housman D. Evidence for a recruitment and sequestration mechanism in Huntington’s disease. Philos Trans R Soc Lond B Biol Sci 354: 1029–1034, 1999.PubMedGoogle Scholar
  88. 88.
    Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739–743, 2001.PubMedGoogle Scholar
  89. 89.
    Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Nail Acad Sci USA 100: 2041–2046, 2003.Google Scholar
  90. 90.
    Ferrante RJ, Kubilus JK, Lee J, Ryu H, Beesen A, Zucker B, et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci 23: 9418–9427, 2003.PubMedGoogle Scholar
  91. 91.
    Ferrante RJ, Ryu H, Kubilus JK, D’Mello S, Sugars KL, Lee J, et al. Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington’s disease. J Neurosci 24: 10335–10342, 2004.PubMedGoogle Scholar
  92. 92.
    Kahlem P, Green H, Djian P. Transglutaminase action imitates Huntington’s disease: selective polymerization of Huntingtin containing expanded polyglutamine. Mol Cell 1: 595–601, 1998.PubMedGoogle Scholar
  93. 93.
    Karpuj MV, Garren H, Slunt H, Price DL, Gusella J, Becher MW, et al. Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington’s disease brain nuclei. Proc Natl Acad Sci USA 96: 7388–7393, 1999.PubMedGoogle Scholar
  94. 94.
    Lesort M, Chun W, Johnson GV, Ferrante RJ. Tissue transglutaminase is increased in Huntington’s disease brain. J Neurochem 73: 2018–2027, 1999.PubMedGoogle Scholar
  95. 95.
    Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R, et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med 8: 143–149, 2002.PubMedGoogle Scholar
  96. 96.
    Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, Kowall NW, et al. Therapeutic effects of cystamine in a murine model of Huntington’s disease. J Neurosci 22: 8942–8950, 2002.PubMedGoogle Scholar
  97. 97.
    Fox JH, Barber DS, Singh B, Zucker B, Swindell MK, Norflus F, et al. Cystamine increases L-cysteine levels in Huntington’s disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation. J Neurochem 91: 413–422, 2004.PubMedGoogle Scholar
  98. 98.
    Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK, et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet 13: 442–449, 1996.PubMedGoogle Scholar
  99. 99.
    Wellington CL, Ellerby LM, Gutekunst CA, Rogers D, Warby S, Graham RK, et al. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington’s disease. J Neurosci 22: 7862–7872, 2002.PubMedGoogle Scholar
  100. 100.
    Gafni J, Hermel E, Young JE, Wellington CL, Hayden MR, Ellerby LM. Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus. J Biol Chem 279: 20211–20220, 2004.PubMedGoogle Scholar
  101. 101.
    Lunkes A, Lindenberg KS, Ben-Haiem L, Weber C, Devys D, Landwehrmeyer GB, et al. Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol Cell 10: 259–269, 2002.PubMedGoogle Scholar
  102. 102.
    Gafni J, Ellerby LM. Calpain activation in Huntington’s disease. J Neurosci 22: 4842–4849, 2002.PubMedGoogle Scholar
  103. 103.
    Hermel E, Gafni J, Propp SS, Leavitt BR, Wellington CL, Young JE, et al. Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington’s disease. Cell Death Differ 11: 424–438, 2004.PubMedGoogle Scholar
  104. 104.
    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6: 797–801, 2000.PubMedGoogle Scholar
  105. 105.
    Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA 100: 10483–10487, 2003.PubMedGoogle Scholar
  106. 106.
    Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PA, et al. Minocycline and doxycycline are not beneficial in a model of Huntington’s disease. Ann Neurol 54: 186–196, 2003.PubMedGoogle Scholar
  107. 107.
    Denovan-Wright EM, Devarajan S, Dursun SM, Robertson HA. Maintained improvement with minocycline of a patient with advanced Huntington’s disease. J Psychopharmacol 16: 393–394, 2002.PubMedGoogle Scholar
  108. 108.
    Bonelli RM, Hodl AK, Hofmann P, Kapfhammer HP. Neuroprotection in Huntington’s disease: a 2-year study on minocycline. Int Clin Psychopharmacol 19: 337–342, 2004.PubMedGoogle Scholar
  109. 109.
    Thomas M, Ashizawa T, Jankovic J. Minocycline in Huntington’s disease: a pilot study. Mov Disord 19: 692–695, 2004.PubMedGoogle Scholar
  110. 110.
    Group HR. Minocycline safety and tolerability in Huntington disease. Neurology 63: 547–549, 2004.Google Scholar
  111. 111.
    Kiechle T, Dedeoglu A, Kubilus J, Kowall NW, Beal MF, Fried-lander RM, et al. Cytochrome C and caspase-9 expression in Huntington’s disease. Neuromolecular Med 1: 183–195, 2002.PubMedGoogle Scholar
  112. 112.
    Sanchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, Yuan J. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22: 623–633, 1999.PubMedGoogle Scholar
  113. 113.
    Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 399: 263–267, 1999.PubMedGoogle Scholar
  114. 114.
    Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348: 1365–1375, 2003.PubMedGoogle Scholar
  115. 115.
    Martinon F, Tschopp J. Inflammatory caspases: linking an intra-cellular innate immune system to autoinflammatory diseases. Cell 117: 561–574, 2004.PubMedGoogle Scholar
  116. 116.
    Zhang Y, Ona VO, Li M, Drozda M, Dubois-Dauphin M, Przed-borski S, et al. Sequential activation of individual caspases, and of alterations in Bcl-2 proapoptotic signals in a mouse model of Huntington’s disease. J Neurochem 87: 1184–1192, 2003.PubMedGoogle Scholar
  117. 117.
    Choo YS, Johnson GV, MacDonald M, Detloff PJ, Lesort M. Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet 2004.Google Scholar
  118. 118.
    Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol 41: 160–165, 1997.PubMedGoogle Scholar
  119. 119.
    Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 22: 1592–1599, 2002.PubMedGoogle Scholar
  120. 120.
    Schilling G, Coonfield ML, Ross CA, Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington’s disease transgenic mouse model. Neurosci Lett 315: 149–153, 2001.PubMedGoogle Scholar
  121. 121.
    Group HS. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 57: 397–404, 2001.Google Scholar
  122. 122.
    Beal MF. Huntington’s disease, energy, and excitotoxicity. Neurobiol Aging 15: 275–276, 1994.PubMedGoogle Scholar
  123. 123.
    Cha JH, Kosinski CM, Kerner JA, Alsdorf SA, Mangiarini L, Davies SW, et al. Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. Proc Natl Acad Sci USA 95: 6480–6485, 1998.PubMedGoogle Scholar
  124. 124.
    Cepeda C, Ariano MA, Calvert CR, Flores-Hemandez J, Chandler SH, Leavitt BR, et al. NMDA receptor function in mouse models of Huntington disease. J Neurosci Res 66: 525–539, 2001.PubMedGoogle Scholar
  125. 125.
    Schiefer J, Sprunken A, Puls C, Luesse HG, Milkereit A, Milkereit E, et al. 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: 246–254, 2004.PubMedGoogle Scholar
  126. 126.
    Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 20: 4389–4397, 2000.PubMedGoogle Scholar
  127. 127.
    Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, et al. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis 8: 479–491, 2001.PubMedGoogle Scholar
  128. 128.
    Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, et al. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J Neurochem 85: 1359–1367, 2003.PubMedGoogle Scholar
  129. 129.
    Verbessern P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, van Leemputte M, et al. Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology 61: 925–930, 2003.Google Scholar
  130. 130.
    Perez-Severiano F, Rios C, Segovia J. Striatal oxidative damage parallels the expression of a neurological phenotype in mice transgenic for the mutation of Huntington’s disease. Brain Res 862: 234–237, 2000.PubMedGoogle Scholar
  131. 131.
    Clifford JJ, Drago J, Natoli AL, Wong JY, Kinsella A, Waddington JL, et al. Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease. Neuroscience 109: 81–88, 2002.PubMedGoogle Scholar
  132. 132.
    Das UN, Vaddadi KS. Essential fatty acids in Huntington’s disease. Nutrition 20: 942–947, 2004.PubMedGoogle Scholar
  133. 133.
    Vaddadi K. Dyskinesias and their treatment with essential fatty acids: a review. Prostaglandins Leukot Essent Fatty Acids 55: 89–94, 1996.PubMedGoogle Scholar
  134. 134.
    Vaddadi KS, Soosai E, Chiu E, Dingjan P. A randomised, placebo-controlled, double blind study of treatment of Huntington’s disease with unsaturated fatty acids. Neuroreport 13: 29–33, 2002.PubMedGoogle Scholar
  135. 135.
    Norflus F, Nanje A, Gutekunst CA, Shi G, Cohen J, Bejarano M, et al. Anti-inflammatory treatment with acetylsalicylate or rofe-coxib is not neuroprotective in Huntington’s disease transgenic mice. Neurobiol Dis 17: 319–325, 2004.PubMedGoogle Scholar
  136. 136.
    Klivenyi P, Ferrante RJ, Gardian G, Browne S, Chabrier PE, Beal MF. Increased survival and neuroprotective effects of BN82451 in a transgenic mouse model of Huntington’s disease. J Neurochem 86: 267–272, 2003.PubMedGoogle Scholar
  137. 137.
    Rodrigues CM, Stieers CL, Keene CD, Ma X, Kren BT, Low WC, et al. Tauroursodeoxycholic acid partially prevents apoptosis induced by 3-nitropropionic acid: evidence for a mitochondrial pathway independent of the permeability transition. J Neurochem 75: 2368–2379, 2000.PubMedGoogle Scholar
  138. 138.
    Rodrigues CM, Sola S, Brito MA, Brondino CD, Brites D, Moura JJ. Amyloid β-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate. Biochem Biophys Res Commun 281: 468–474, 2001.PubMedGoogle Scholar
  139. 139.
    Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington’s disease. Proc Natl Acad Sci USA 99: 10671–10676, 2002.PubMedGoogle Scholar
  140. 140.
    Carmichael J, Sugars KL, Bao YP, Rubinsztein DC. Glycogen synthase kmase-3β inhibitors prevent cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J Biol Chem 277: 33791–33798, 2002.PubMedGoogle Scholar
  141. 141.
    Wood NI, Morton AJ. Chronic lithium chloride treatment has variable effects on motor behaviour and survival of mice transgenic for the Huntington’s disease mutation. Brain Res Bull 61: 375–383, 2003.PubMedGoogle Scholar
  142. 142.
    Rebec GV, Barton SJ, Ennis MD. Dysregulation of ascorbate release in the striatum of behaving mice expressing the Huntington’s disease gene. J Neurosci 22: RC202, 2002.PubMedGoogle Scholar
  143. 143.
    Rebec GV, Barton SJ, Marseilles AM, Collins K. Ascorbate treatment attenuates the Huntington behavioral phenotype in mice. Neuroreport 14: 1263–1265, 2003.PubMedGoogle Scholar
  144. 144.
    Alberch J, Perez-Navarro E, Canals JM. Neurotrophic factors in Huntington’s disease. Prog Brain Res 146: 195–229, 2004.PubMedGoogle Scholar
  145. 145.
    Popovic N, Maingay M, Kirik D, Brundin P. Lentiviral gene delivery of GDNF into the striatum of R6/2 Huntington mice fails to attenuate behavioral and neuropathological changes. Exp Neurol 193: 65–74, 2005.PubMedGoogle Scholar
  146. 146.
    Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293: 493–498, 2001.PubMedGoogle Scholar
  147. 147.
    Baquet ZC, Gorski JA, Jones KR. Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J Neurosci 24: 4250–4258, 2004.PubMedGoogle Scholar
  148. 148.
    Canals JM, Pineda JR, Torres-Peraza JF, Bosch M, Martin-Ibanez R, Munoz MT, et al. Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J Neurosci 24: 7727–7739, 2004.PubMedGoogle Scholar
  149. 149.
    Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Rangone H, Cordelieres FP, et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118: 127–138, 2004.PubMedGoogle Scholar
  150. 150.
    Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35: 76–83, 2003.PubMedGoogle Scholar
  151. 151.
    Ferrer I, Goutan E, Marin C, Rey MJ, Ribalta T. Brain-derived neurotrophic factor in Huntington disease. Brain Res 866: 257–261, 2000.PubMedGoogle Scholar
  152. 152.
    Cepeda C, Starling AJ, Wu N, Nguyen OK, Uzgil B, Soda T, et al. Increased GABAergic function in mouse models of Huntington’s disease: reversal by BDNF. J Neurosci Res 78: 855–867, 2004.PubMedGoogle Scholar
  153. 153.
    van Dellen A, Deacon R, York D, Blakemore C, Hannan AJ. Anterior cingulate cortical transplantation in transgenic Huntington’s disease mice. Brain Res Bull 56: 313–318, 2001.PubMedGoogle Scholar
  154. 154.
    Dunnett SB, Carter RJ, Watts C, Tones EM, Mahal A, Mangiarini L, et al. Striatal transplantation in a transgenic mouse model of Huntington’s disease. Exp Neurol 154: 31–40, 1998.PubMedGoogle Scholar
  155. 155.
    Carter RJ, Hunt MJ, Morton AJ. Environmental stimulation increases survival in mice transgenic for exon 1 of the Huntington’s disease gene. Mov Disord 15: 925–937, 2000.PubMedGoogle Scholar
  156. 156.
    Hockly E, Cordery PM, Woodman B, Mahal A, van Dellen A, Blakemore C, et al. Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann Neurol 51: 235–242, 2002.PubMedGoogle Scholar
  157. 157.
    Glass M, van Dellen A, Blakemore C, Hannan AJ, Faull RL. Delayed onset of huntington’s disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience 123: 207–212, 2004.PubMedGoogle Scholar
  158. 158.
    Schilling G, Savonenko AV, Coonfield ML, Morton JL, Vorovich E, Gale A, et al. Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice. Exp Neurol 187: 137–149, 2004.PubMedGoogle Scholar
  159. 159.
    Spires TL, Grote HE, Varshney NK, Cordery PM, van Dellen A, Blakemore C, et al. Environmental enrichment rescues protein deficits in a mouse model of Huntington’s disease, indicating a possible disease mechanism. J Neurosci 24: 2270–2276, 2004.PubMedGoogle Scholar
  160. 160.
    Curtis MA, Penney EB, Pearson AG, van Roon-Mom WM, Butterworth NJ, Dragunow M, et al. Increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain. Proc Natl Acad Sci USA 100: 9023–9027, 2003.PubMedGoogle Scholar
  161. 161.
    Gil JM, Leist M, Popovic N, Brundin P, Petersen A. Asialoerythropoietin is not effective in the R6/2 line of Huntington’s disease mice. BMC Neurosci 5: 17, 2004.PubMedGoogle Scholar
  162. 162.
    Lazic SE, Grote H, Armstrong RJ, Blakemore C, Hannan AJ, van Dellen A, et al. Decreased hippocampal cell proliferation in R6/1 Huntington’s mice. Neuroreport 15: 811–813, 2004.PubMedGoogle Scholar
  163. 163.
    Erbayraktar S, Grasso G, Sfacteria A, Xie QW, Coleman T, Kreilgaard M, et al. Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci USA 100: 6741–6746, 2003.PubMedGoogle Scholar
  164. 164.
    Menalled LB. Knock-in mouse models of huntington’s disease. NeuroRx 2: 465–470, 2005.PubMedGoogle Scholar
  165. 165.
    Slow EJ, Van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12: 1555–1567, 2003.PubMedGoogle Scholar
  166. 166.
    Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, et al. Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 10: 137–144, 2001.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc 2005

Authors and Affiliations

  1. 1.Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical ScienceBMC A10LundSweden

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