Acta Neuropathologica

, Volume 115, Issue 1, pp 55–69 | Cite as

Huntington disease models and human neuropathology: similarities and differences

  • Jean Paul G. VonsattelEmail author


Huntington disease (HD) occurs only in humans. Thus, its natural pathogenesis takes place exclusively within the human brains expressing the causative, mutated protein huntingtin (mhtt). The techniques applicable to postmortem human HD brains are inadequate for investigating the cellular pathogenesis. The creation of genetically engineered animals represents a critical moment in neuroscience. Monitoring the actions of either normal, or abnormal proteins at subcellular levels, and at different time points is now possible thanks to these models. They are the necessary substitutes to investigate the wild type (whtt), or mhtt. The postmortem neuropathologic phenotype of the human HD is well documented. Its pattern and spectrum are highly predictable. From this point of view, the existent models do not exhibit the phenotypic constellation of changes seen in the human HD brains. On one hand, this deficit reflects the limitations of the methods of evaluation used in a clinical setting. On the other hand, it highlights the limitations of the animals. The validity of the models probably should be measured by their capacity of reproducing the cellular dysfunctions of HD rather than the phenotype of the postmortem human brains. Although not perfect, these models are essential for modeling the human disease in cells, which is not feasible with postmortem human HD brains. Nonetheless, their relevance to the patient population remains to be determined. Ultimately needed are means preventing the disease to occur, the discovery of which probably depends on these models.


Huntington disease Transgenic mouse Knockin mouse Mice gene carriers of the HD mutation 



This work was supported by grants from the National Institutes of Health and National Institute on Aging: P01-AG07232, R37-AG15473, and P50-AG08702, the Hereditary Disease Foundation, and the Iseman Fund. The author is grateful to Lisle Merriman for her editorial support, and to Mkeba Cason, Etty Cortes, M.D., and Katerina Mancevska for their help. The New York Brain Bank (NYBB) is especially thankful to the numerous pathologists who referred case material, and to the families of the patients for providing brain tissue for research.


  1. 1.
    Albin RL (1995) Selective neurodegeneration in Huntington’s disease. Ann Neurol 38:835–836 PubMedGoogle Scholar
  2. 2.
    Bates GP, Gonitel R (2006) Mouse models of triplet repeat diseases. Mol Biotech 32:147–158 Google Scholar
  3. 3.
    Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38:357–366 PubMedGoogle Scholar
  4. 4.
    Beal MF, Ferrante RJ (2004) Experimental therapeutics in transgenic mouse models of Huntington’s disease. Nat Rev Neurosci 5:373–384. doi: 10.1038/nrn1386 PubMedGoogle Scholar
  5. 5.
    Becher MW, Kotzuk JA, Sharp AH, Davies SW, Bates GP, Price DL, Ross CA (1998) Intranuclear neuronal inclusions in Huntington’s disease and dentatorubropallidoluysian atrophy: correlation between the density of inclusions and IT 15 CAG triplet repeat length. Neurobiol Dis 4:387–397 PubMedGoogle Scholar
  6. 6.
    Borrell-Pagès M, Zala D, Humbert S, Saudou F (2006) Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies. Cell Mol Life Sci 63:2642–2660 PubMedGoogle Scholar
  7. 7.
    Braak H, Braak E (1992) Allocortical involvement in Huntington’s disease. Neuropathol Appl Neurobiol 18:539–547PubMedGoogle Scholar
  8. 8.
    Brignull HR, Moore FE, Tang SJ, Morimoto RI (2006) Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model. J Neurosci 2006:7597–7606. doi: 10.1523/JNEUROSCI.0990-06.2006 Google Scholar
  9. 9.
    Brons IGM, Smithers LE, Trotter MWB, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes SM, Howlett SK, Clarkson A, Ahrlund-Richter L, Pedersen RA, Vallier L (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature. doi: 10.1038/nature05950
  10. 10.
    Byers RK, Gilles FH, Fung C (1973) Huntington’s disease in children. Neurology 23:561–569 PubMedGoogle Scholar
  11. 11.
    Campbell AMG, Corner B, Norman RM, Urich H (1961) The rigid form of Huntington’s disease. J Neurol Neurosurg Psychiatry 24:71–77PubMedGoogle Scholar
  12. 12.
    Carpenter MB, Sutin J (eds) (1983) Human neuroanatomy, 8 edn. Williams & Wilkins, Baltimore/London, pp 579–586Google Scholar
  13. 13.
    Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 6:919–930. doi: 10.1038/nrn1806 PubMedGoogle Scholar
  14. 14.
    Cha J-H (2000) Transcriptional dysregulation in Huntington’s disease. Trends Neurosci 23:387–392PubMedGoogle Scholar
  15. 15.
    Curtis MA, Penney EB, Pearson AG, van Roon-Mom MC, Butterworth NJ, Dragunow M, Connor B, Faull RLM (2003) Increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain. Proc Natl Acad Sci USA 100:9023–9027. doi: 10.1073/pnas.1532244100 PubMedGoogle Scholar
  16. 16.
    Curtis MA, Waldvogel HJ, Synek B, Faull RLM (2005) A histochemical and immunohistochemical analysis of the subependymal layer in the normal and Huntington’s disease brain. J Chem Neutoanat 30:55–66. doi: 10.1016/j.jchemneu.2005.05.001 Google Scholar
  17. 17.
    Davies SW, Turmaine M, Cozens BA, DiFiglia M, Sharp AH, Ross CA, Scherzinger E, Wanker EE, Mangiarini L, Bates GP (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548 PubMedGoogle Scholar
  18. 18.
    de la Monte SM, Vonsattel JP, Richardson EP Jr (1988) Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington’s disease. J Neuropathol Exp Neurol 47:516–525 Google Scholar
  19. 19.
    DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993 PubMedGoogle Scholar
  20. 20.
    Ferrante RJ, Kowall NW, Beal MF, Martin JB, Bird ED, Richardson EP (1987) Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington’s disease. J Neuropathol Exp Neurol 46:12–27 PubMedGoogle Scholar
  21. 21.
    Folstein SE (ed) (1989) The diagnosis of Huntington’s disease. In: Huntington’s disease. A disorder of families. The Johns Hopkins University Press, Baltimore, pp 125–148Google Scholar
  22. 22.
    Forno LS, Jose C (1973) Huntington’s chorea: a pathological study. Adv Neurol 1:453–470Google Scholar
  23. 23.
    Gil JMAC, Mohapel P, Araújo IM, Popovic N, Li J-Y, Brundin P, Petersén A (2005) Reduced hippocampal neurogenesis in R6/2 transgenic Huntington’s disease mice. Neurobiol Dis 20:744–751 PubMedGoogle Scholar
  24. 24.
    Gómez-Tortosa E, MacDonald ME, Friend JC, Taylor SAM, Weiler LJ, Cupples LA, Srinidhi J, Gusella JF, Bird ED, Vonsattel J-P, Myers RH (2001) Quantitative neuropathological changes in presymptomatic Huntington’s disease. Ann Neurol 49:29–34 PubMedGoogle Scholar
  25. 25.
    Gourfinkel-An I, Cancel G, Duyckaerts C, Faucheux B, Hauw J-J, Trottier Y, Brice A, Agid Y, Hirsch EC (1998) Neuronal distribution of intranuclear inclusions in Huntington’s disease with adult onset. Neuroreport 9:1823–1826 PubMedGoogle Scholar
  26. 26.
    Gourfinkel-An I, Cancel G, Trottier Y, Devys D, Tora L, Lutz Y, Imbert G, Saudou F, Stevanin G, Agid Y, Brice A, Mandel J-L, Hirsch EC (1997) Differential distribution of the normal and mutated forms of huntingtin in the human brain. Ann Neurol 42:712–719 PubMedGoogle Scholar
  27. 27.
    Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby SC, Doty CN, Roy S, Wellington CL, Leavitt BR, Raymond LA, Nicholson DW, Hayden MR (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125:1179–1191. doi: 10.1016/j.cell.2006.04.026 PubMedGoogle Scholar
  28. 28.
    Graveland GA, Williams RS, DiFiglia M (1985) Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science 227:770–773 PubMedGoogle Scholar
  29. 29.
    Greenamyre JT (2007) Huntington’s disease—making connections. N Engl J Med Line 356:518–520 PubMedGoogle Scholar
  30. 30.
    Group: The Huntington’s Disease Collaborative Research Group; MacDonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C, Srinidhi L, Barnes G, Taylor SA, James M, Groot N, MacFarlane H, Jenkins B, Anderson MA, Wexler NS, Gusella JF (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983 Google Scholar
  31. 31.
    Gutekunst C-A, Levey AI, Heilman GJ, Whaley WL, Yi H, Nash NR, Rees HD, Madden JJ, Hersch SM (1995) Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc Natl Acad Sci USA 92:8710–8714 PubMedGoogle Scholar
  32. 32.
    Gutekunst C-A, Li S-H, Mulroy JS, Kuemmerle S, Jones R, Rye D, Ferrante RJ, Hersch SM, Li X-J (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 19:2522–2534 PubMedGoogle Scholar
  33. 33.
    Hallervorden J (1957) Huntingtonsche Chorea (Chorea chronica progressiva hereditaria). In: Handbuch der speziellen pathologischen Anatomie und Histologie (XIII/1 Bandteil A). Springer, Berlin, pp 793–822Google Scholar
  34. 34.
    Halliday GM, McRitchie DA, Macdonald V, Double KL, Trent RJ, McCusker E (1998) Regional specificity of brain atrophy in Huntington’s disease. Exp Neurol 154:663–672 PubMedGoogle Scholar
  35. 35.
    Harper PS, Morris MR, Quarrell OWJ, Shaw DJ, Tyler A, Youngman S (1991) The clinical neurology of Huntington’s disease. In: Huntington’s disease. Major problems in neurology, vol 22. W.B. Saunders, London, pp 37–80Google Scholar
  36. 36.
    Hedreen JC, Peyser CE, Folstein SE, Ross CA (1991) Neuronal loss in layers V and VI of cerebral cortex in Huntington’s disease. Neurosci Lett 133:257–261 PubMedGoogle Scholar
  37. 37.
    Hilditch-Maguire P, Trettel F, Passani LA, Auerbach A, Persichetti F, MacDonald M (2000) Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet 9:2789–2797 PubMedGoogle Scholar
  38. 38.
    Hockly E, Cordery PM, Woodman B, Mahal A, van Dellen A, Blakemore C, Lewis CM, Hannan AJ, Bates GP (2002) Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann Neurol 51:235–242. doi: 10.1002/ana.10094 PubMedGoogle Scholar
  39. 39.
    Hodgson JG, Agopyan N, Gutekunst C-A, Leavitt BR, LePiane F, Singaraja R, Smith DJ, Bissada N, McCutcheon K, Nasir J, Jamot L, Li X-J, Stevens ME, Rosemond E, Roder JC, Phillips AG, Rubin EM, Hersch SM, Hayden MR (1999) A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23:182–192 Google Scholar
  40. 40.
    Huang CC, Faber PW, Persichetti F, Mittal V, Vonsattel J-P, MacDonald ME, Gusella JF (1998) Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat Cell Mol Genet 24:217–233 PubMedGoogle Scholar
  41. 41.
    Ishiguro H, Yamada K, Sawada H, Nishii K, Ichino N, Sawada M, Kurosawa Y, Matsushita N, Kobayashi K, Goto J, Hashida H, Masuda N, Kanazawa I, Nagatsu T (2001) Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington’s disease gene. J Neurosci Res 65:289–297 PubMedGoogle Scholar
  42. 42.
    Jervis GA (1963) Huntington’s chorea in childhood. Arch Neurol 9:244–257 PubMedGoogle Scholar
  43. 43.
    Kegel KB, Meloni AR, Yi Y, Kim YJ, Doyle E, Cuiffo BG, Sapp E, Wang Y, Qin Z-H, Chen JD, Nevins JR, Aronin N, DiFiglia M (2002) Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription. J Biol Chem 277:7466–7476 PubMedGoogle Scholar
  44. 44.
    Kennedy L, Shelbourne PF (2000) Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington’s disease? Hum Mol Genet 9:2539–2544 PubMedGoogle Scholar
  45. 45.
    Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B, Bassett A, Almqvist E, Bird TD, Hayden MR (1994) A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med Line 330:1401–1406 Google Scholar
  46. 46.
    Kuemmerle S, Gutekunst C-A, Klein AM, Li X-J, Li S-H, Beal MF, Hersch SM, Ferrante RJ (1999) Huntingtin aggregates may not predict neuronal death in Huntington’s disease. Ann Neurol 46:842–849 PubMedGoogle Scholar
  47. 47.
    Kuhn A, Goldstein DR, Hodges A, Strand AD, Sengstag T, Kooperberg C, Becanovic K, Pouladi MA, Sathasivam K, Cha J-HJ, Hannan AJ, Hayden MR, Leavitt BR, Dunnett SB, Ferrante RJ, Albin R, Shelbourne P, Delorenzi M, Augood SJ, Faull RLM, Olson JM, Bates GP, Jones L, Luthi-Carter R (2007) Mutant huntingtin’s effects on striatal gene expression in mice recapitulate changes observed in human Huntington’s disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage. Hum Mol Genet 16:1845–1861. doi: 10.1093/hmg/ddm133 PubMedGoogle Scholar
  48. 48.
    Landwehrmeyer GB, McNeil SM, Dure LS IV, Ge P, Aizawa H, Huang Q, Ambrose CM, Duyao MP, Bird ED, Bonilla E, de Young M, Avila-Gonzales AJ, Wexler NS, DiFiglia M, Gusella JF, MacDonald ME, Penney JB, Young AB, Vonsattel JP (1995) Huntington’s disease gene: regional and cellular expression in brain of normal and affected individuals. Ann Neurol 37:218–230 PubMedGoogle Scholar
  49. 49.
    Lange H, Thörner G, Hopf A, Schröder KF (1976) Morphometric studies of the neuropathological changes in choreatic diseases. J Neurol Sci 28:401–425 PubMedGoogle Scholar
  50. 50.
    Lazic SE, Grote H, Armstrong JE, Blakemore C, Hannan AJ, van Dellen A, Barker RA (2004) Decreased hippocampal cell proliferation in R6/1 Huntington’s mice. Neuroreport 15:811–813. doi: 10.1097/01.wnr.0000122486.43641.90 PubMedGoogle Scholar
  51. 51.
    Lazic SE, Grote HE, Blakemore C, Hannan AJ, van Dellen A, PhillipsW, Barker RA (2006) Neurogenesis in the R6/1 transgenic mouse model of Huntington’s disease: effects of environmental enrichment. Eur J Neurosci 23:1829–1838. doi: 10.1111/j.1460-9568.2006.04715.x PubMedGoogle Scholar
  52. 52.
    Levine MS, Cepeda C, Hickey MA, Fleming SM, Chesselet M-F (2004) Genetic mouse models of Huntington’s and Parkinson’s disease: illuminating but imperfect. Trends Neurosci 27:691–697 PubMedGoogle Scholar
  53. 53.
    Levine MS, Klapstein GJ, Koppel A, Gruen E, Cepeda C, Vargas ME, Jokel ES, Carpenter EM, Zanjani H, Hurst RS, Efstratiadis A, Zeitlin S, Chesselet M-F (1999) 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 PubMedGoogle Scholar
  54. 54.
    Li H, Li S-H, Johnston H, Shelbourne PF, Li S-J (2000) Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nat Genet 25:385–389 PubMedGoogle Scholar
  55. 55.
    Lin C-H, Tallaksen-Greene S, Chien W-M, Cearley JA, Jackson WS, Crouse AB, Ren S, Li X-J, Albin RL, Detloff PJ (2001) Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 10:137–144 PubMedGoogle Scholar
  56. 56.
    Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795. doi: 10.1038/nature05292 PubMedGoogle Scholar
  57. 57.
    Luthi-Carter R, Hanson SA, Strand AD, Bergstrom DA, Chun W, Peters NL, Woods AM, Chan EY, Kooperberg C, Krainc D, Young AB, Tapscott SJ, Olson JM (2002) Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum Mol Genet 11:1911–1926 PubMedGoogle Scholar
  58. 58.
    Maat-Schieman MLC, Dorsman JC, Smoor MA, Siesling S, van Duinen SG, Verschuuren JGM, den Dunnen JT, van Ommen G-JB, Roos AC (1999) Distribution of inclusions in neuronal nuclei and dystrophic neurites in Huntington disease brain. J Neuropathol Exp Neurol 58:129–137PubMedGoogle Scholar
  59. 59.
    Macdonald V, Halliday GM, Trent RJ, McCusker EA (1997) Significant loss of pyramidal neurons in the angular gyrus of patients with Huntington’s disease. Neuropathol Appl Neurobiol 23:492–495 PubMedGoogle Scholar
  60. 60.
    Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506 PubMedGoogle Scholar
  61. 61.
    Margolis RL, Roos CA (2001) Expansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases. Trends Mol Med 7:479–482. doi: 10.1016/S1471-4914(01)02179-7 PubMedGoogle Scholar
  62. 62.
    Markham CH, Knox JW (1965) Observations on Huntington’s chorea in childhood. J Pediatr 67:46–57 PubMedGoogle Scholar
  63. 63.
    McCaughey WTE (1961) The pathologic spectrum of Huntington’s chorea. J Nerv Ment Dis 133:91–103 CrossRefGoogle Scholar
  64. 64.
    Menalled LB, Chesselet M-F (2002) Mouse models of Huntington’s disease. Trends Pharmacol Sci 23:32–39 PubMedGoogle Scholar
  65. 65.
    Menalled LB, Sison JD, Dragatsis I, Zeitlin S, Chesselet M-F (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 465:11–26 PubMedGoogle Scholar
  66. 66.
    Menalled LB, Sison JD, Wu U, Olivieri M, Li X-J, Li H, Zeitlin S, Chesselet M-F (2002) Early motor dysfunction and striosomal distribution of huntingtin microaggregates in Huntington’s disease knock-in mice. J Neurosci 22:8266–8276 PubMedGoogle Scholar
  67. 67.
    Myers RH, Leavitt J, Farrer LA, Jagadeesh J, McFarlane H, Mastromauro CA, Mark RJ, Gusella JF (1989) Homozygote for Huntington disease. Am J Hum Genet 45:615–618 PubMedGoogle Scholar
  68. 68.
    Myers RH, Vonsattel JP, Paskevich PA, Kiely DK, Stevens TJ, Cupples LA, Richardson EP Jr, Bird ED (1991) Decreased neuronal and increased oligodendroglial densities in Huntington’s disease caudate nucleus. J Neuropathol Exp Neurol 50:729–742 PubMedGoogle Scholar
  69. 69.
    Myers RH, Vonsattel JP, Stevens TJ, Cupples LA, Richardson EP, Martin JB, Bird ED (1988) Clinical and neuropathologic assessment of severity in Huntington’s disease. Neurology 38:341–347 PubMedGoogle Scholar
  70. 70.
    Nance MA, Mathias-Hagen V, Breningstall G, Wick MJ, McGlennen RC (1999) Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington’s disease. Neurology 52:392–394 PubMedGoogle Scholar
  71. 71.
    Nucifora FC, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM, Ross CA (2001) Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science 291:2423–2428 PubMedGoogle Scholar
  72. 72.
    Obrietan K, Hoyt KR (2004) CRE-mediated transcription is increased in Huntington’s disease transgenic mice. J Neurosci 24:791–796. doi: 10.1523/JNEUROSCI.3493-03-2004 PubMedGoogle Scholar
  73. 73.
    Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621. doi: 10.1146/annurev.neuro.29.051605.113042 PubMedGoogle Scholar
  74. 74.
    Paulson HL (1999) Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold. Hum Genet 64:339–345 Google Scholar
  75. 75.
    Phillips W, Morton AJ, Barker RA (2005) Abnormalities of neurogenesis in the R6/2 mouse model of Huntington’s disease are attributable to the in vivo microenvironment. J Neurosci 25:11564–11576. doi: 10.1523/JNEUROSCI.3796-05.2005 PubMedGoogle Scholar
  76. 76.
    Project: The US—Venezuela Collaborative Research Project, Wexler NS (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci USA 101:3498–3503 PubMedGoogle Scholar
  77. 77.
    Reddy PH, Williams M, Charles V, Garrett L, Pike-Buchanan L, Whetsell WO Jr, Miller G, Tagle DA (1998) Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet 20:198–202 PubMedGoogle Scholar
  78. 78.
    Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB (1988) Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci USA 85:5733–5737 PubMedGoogle Scholar
  79. 79.
    Richardson EP Jr (1990) Huntington’s disease: some recent neuropathological studies. Neuropathol Appl Neurobiol 16:451–460 PubMedGoogle Scholar
  80. 80.
    Richfield EK, Maguire-Zeiss KA, Cox C, Gilmore J, Voorn P (1995) Reduced expression of preproenkephalin in striatal neurons from Huntington’s disease patients. Ann Neurol 37:335–343 PubMedGoogle Scholar
  81. 81.
    Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu G-Q, Mucke L (2007) Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754. doi: 10.1126/science.1141736 PubMedGoogle Scholar
  82. 82.
    Robitaille Y, Lopes-Cendes I, Becher M, Rouleau G, Clark AW (1997) The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 7:901–926 PubMedGoogle Scholar
  83. 83.
    Roos RAC, Pruyt JFM, de Vries J, Bots GTAM (1985) Neuronal distribution in the putamen in Huntington’s disease. J Neurol Neurosurg Psychiatry 48:422–425 PubMedCrossRefGoogle Scholar
  84. 84.
    Rosenberg RN (1996) DNA-triplet repeats and neurologic disease. N Engl J Med Line 335:1222–1224 Google Scholar
  85. 85.
    Rubinsztein DC (2002) Lessons from animal models of Huntington’s disease. Trends Genet 18:202–209 PubMedGoogle Scholar
  86. 86.
    Rubinsztein DC, Carmichael J (2003) Huntington’s disease: molecular basis of neurodegeneration. Expert Rev Mol Med 5:1–21. doi: 10.1017/S1462399403006549 PubMedGoogle Scholar
  87. 87.
    Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman J-J, Chotai K, Connarty M, Craufurd D, Curtis A, Curtis D, Davidson MJ, Differ A-M, Dode C, Dodge A, Frontali M, Ranen NG, Stine OC, Sherr M, Abbott MH, Franz ML, Graham CA, Harper PS, Hedreen JC, Jackson A, Kaplan J-C, Losekoot M, MacMillan JC, Morrison P, Trottier Y, Novelletto A, Simpson S, Theilmann J, Whittaker JL, Folstein SE, Ross CA, Hayden MR (1996) Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am J Hum Genet 59:16–22 PubMedGoogle Scholar
  88. 88.
    Sapp E, Ge P, Aizawa H, Bird E, Penney J, Young AB, Vonsattel J-P, DiFiglia M (1995) Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington’s disease using high resolution image analysis. Neuroscience 64:397–404 PubMedGoogle Scholar
  89. 89.
    Sapp E, Kegel KB, Aronin N, Yohyama K, Uchiyama Y, Bhide P, Vonsattel JP, DiFiglia M (1999) Microglia accumulate in the HD striatum and cortex. Soc Neurosci 25:829 Google Scholar
  90. 90.
    Sapp E, Penney J, Young AB, Aronin N, Vonsattel J-P, DiFiglia M (1999) Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. J Neuropathol Exp Neurol 58:165–173 PubMedGoogle Scholar
  91. 91.
    Sapp E, Schwarz C, Chase K, Bhide PG, Young AB, Penney J, Vonsattel JP, Aronin N, DiFiglia M (1997) Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol 42:604–612 PubMedGoogle Scholar
  92. 92.
    Sathasivam K, Hobbs C, Turmaine M, Mangiarini L, Mahal A, Bertaux F, Wanker EE, Doherty P, Davies SW, Bates GP (1999) Formation of polyglutamine inclusions in non-CNS tissue. Hum Mol Genet 8:813–822 PubMedGoogle Scholar
  93. 93.
    Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, Bates GP, Davies SW, Lehrach H, Wanker EE (1997) Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90:549–558 PubMedGoogle Scholar
  94. 94.
    Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, Slunt HH, Ratovitski T, Cooper JK, Jenkins NA, Copeland NG, Price DL, Ross CA, Borchelt DR (1999) Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet 8:397–407 PubMedGoogle Scholar
  95. 95.
    Shelbourne PF, Killeen N, Hevner RF, Johnston HM, Tecott L, Lewandoski M, Ennis M, Ramirez L, Li Z, Iannicola C, Littman DR, Myers RM (1999) A Huntington’s disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum Mol Genet 8:763–774 PubMedGoogle Scholar
  96. 96.
    Slow EJ, Graham RK, Osmand AP, Devon RS, Lu G, Deng Y, Pearson J, Vaid K, Bissada N, Wetzel R, Leavitt BR, Hayden MR (2005) Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc Natl Acad Sci USA 102:11402–11407 PubMedGoogle Scholar
  97. 97.
    Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Bissada N, Hossain SM, Yang Y-Z, Li X-J, Simpson EM, Gutekunst C-A, Leavitt BR, Hayden MR (2003) Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12:1555–1567 PubMedGoogle Scholar
  98. 98.
    Sotrel A, Paskevich PA, Kiely DK, Bird ED, Williams RS, Myers RH (1991) Morphometric analysis of the prefrontal cortex in Huntington’s disease. Neurology 41:1117–1123 PubMedGoogle Scholar
  99. 99.
    Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi A-C, Simpson SA, Delatycki M, Maglione V, Hayden MR, Di Donato S (2003) Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain 126:946–955 PubMedGoogle Scholar
  100. 100.
    Sugars KL, Rubinsztein DC (2003) Transcriptional abnormalities in Huntington disease. Trends Genet 19:233–238. doi: 10.1016/S0168-9525(03)00074-X PubMedGoogle Scholar
  101. 101.
    Telenius H, Kremer B, Goldberg YP, Theilmann J, Andrew SE, Zeisler J, Adam S, Greenberg C, Ives EJ, Clarke LA, Hayden MR (1994) Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat Genet 6:409–414 PubMedGoogle Scholar
  102. 102.
    Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL, Gardner RL, McKay RDG (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature. doi: 10.1038/nature05972
  103. 103.
    Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L, Agid Y, Brice A, Mandel J-L (1995) Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 378:403–406 PubMedGoogle Scholar
  104. 104.
    Turmaine M, Raza A, Mahal A, Mangiarini L, Bates GP, Davies SW (2000) Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington’s disease. Proc Natl Acad Sci USA 97:8093–8097 PubMedGoogle Scholar
  105. 105.
    van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ (2000) Delaying he onset of Huntington’s in mice. Nature 404:721–722 PubMedGoogle Scholar
  106. 106.
    von Hörsten S, Schmitt I, Nguyen HP, Holzmann C, Schmidt T, Walther T, Bader M, Pabst R, Kobbe P, Krotova J, Stiller D, Kask A, Vaarmann A, Rathke-Hartlieb S, Schulz JB, Grasshoff U, Bauer I, Menezes AM, Vieira-Saecker AMM, Paul M, Jones L, Lindenberg KS, Landwehrmeyer B, Bauer A, Li X-J, Riess O (2003) Transgenic rat model of Huntington’s disease. Hum Mol Genet 12. doi: 10.1093/hmg/ddg075
  107. 107.
    Vonsattel J-P, Myers RH, Bird ED, Ge P, Richardson EP Jr (1992) Maladie de Huntington: sept cas avec îlots néostriataux relativement préservés. Rev Neurol 148:107–116 PubMedGoogle Scholar
  108. 108.
    Vonsattel J-P, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577 PubMedGoogle Scholar
  109. 109.
    Vonsattel J-PG, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384 PubMedCrossRefGoogle Scholar
  110. 110.
    Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Arroyo MAR, Penchaszadeh GK, Moreno H, Gibbons K, Faryniarz A, Hobbs W, Anderson MA, Bonilla E, Conneally PM, Gusella JF (1987) Homozygotes for Huntington’s disease. Nature 326:194–197 PubMedGoogle Scholar
  111. 111.
    Wheeler VC, White JK, Gutekunst C-A, Vrbanac V, Weaver M, Li X-J, Li S-H, Yi H, Vonsattel J-P, Gusella JF, Hersch S, Auerbach W, Joyner AL, MacDonald ME (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 9:503–513 PubMedGoogle Scholar
  112. 112.
    White JK, Auerbach W, Duyao MP, Vonsattel J-P, Gusella JF, Joyner AL, MacDonald ME (1997) Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat Genet 17:404–410 PubMedGoogle Scholar
  113. 113.
    Yu Z-X, Li S-H, Evans J, Pillarisetti A, Li H, Li X-J (2003) Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington’s disease. J Neurosci 23:2193–2202 PubMedGoogle Scholar
  114. 114.
    Zalneraitis EL, Landis DMD, Richardson EP Jr, Selkoe DJ (1981) A comparison of astrocytic structure in cerebral cortex and striatum in Huntington’s disease. Neurology 31:151Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.The Department of Pathology in the College of Physicians and Surgeons, The Taub Institute for Research on Alzheimer’s Disease and the Aging BrainColumbia UniversityNew YorkUSA
  2. 2.The New York Brain Bank/Taub InstituteColumbia University, Children’s HospitalNew YorkUSA

Personalised recommendations