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Neurogenetics

, Volume 5, Issue 1, pp 9–17 | Cite as

Genetic and environmental factors in the pathogenesis of Huntington’s disease

  • Anton van DellenEmail author
  • Anthony J. Hannan
Review Article

Abstract.

Huntington’s disease is a fatal inherited disorder in which there is progressive neurodegeneration in specific brain areas, mainly the striatum and cerebral cortex, producing motor, cognitive, and psychiatric symptoms. The trinucleotide repeat mutation involved is common to many other brain diseases, which may therefore involve similar mechanisms of pathogenesis. We are beginning to understand how a CAG trinucleotide repeat expansion in the disease gene, encoding an expanded polyglutamine tract, induces neuronal dysfunction and symptomatology in Huntington’s disease. Recent evidence that environmental factors modify the onset and progression of neurodegeneration has shed new light on Huntington’s disease and other devastating brain diseases. This review focuses on genetic mediators, environmental modulators, and associated gene-environment interactions in the pathogenesis of Huntington’s disease.

Keywords

Huntington’s disease CAG trinucleotide repeat expansion Neurodegeneration Environmental and genetic modulators Polyglutamine 

Notes

Acknowledgements.

We are indebted to Tara Spires, Nektarios Mazarakis, Helen Grote, and Colin Blakemore for their contributions to the research described in this article. We also thank Carolyn Hannan, Monique Howard, and Caitlin McOmish for comments on the manuscript. The author’s research has been supported by the Rhodes Trust (A.D.), NHMRC (A.J.H.), Oxford Nuffield Medical Trust (A.J.H.), Royal Society, MRC (UK), and Wellcome Trust (A.J.H.).

References

  1. 1.
    Richards RI, Sutherland GR (1992) Dynamic mutations: a new class of mutations causing human disease. Cell 70:709–712PubMedGoogle Scholar
  2. 2.
    Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983PubMedGoogle Scholar
  3. 3.
    Huntington G (1872) Med Surg Reporter 26:317Google Scholar
  4. 4.
    Bates G, Harper PS, Jones L (2002) Huntington’s disease, 3rd edn. Oxford University Press, OxfordGoogle Scholar
  5. 5.
    Leeflang EP, Tavare S, Marjoram P, Neal CO, Srinidhi J, MacFarlane H, MacDonald ME, Gusella JF, Young M de, Wexler NS, Arnheim N (1999) Analysis of germline mutation spectra at the Huntington’s disease locus supports a mitotic mutation mechanism. Hum Mol Genet 8:173–183CrossRefPubMedGoogle Scholar
  6. 6.
    Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M, et al (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–392PubMedGoogle Scholar
  7. 7.
    Mangiarini L, Sathasivam K, Mahal A, Mott R, Seller M, Bates GP (1997) Instability of highly expanded CAG repeats in mice transgenic for the Huntington’s disease mutation. Nat Genet 15:197–200PubMedGoogle Scholar
  8. 8.
    MacDonald ME, Vonsattel JP, Shrinidhi J, Couropmitree NN, Cupples LA, Bird ED, Gusella JF, Myers RH (1999) Evidence for the GluR6 gene associated with younger onset age of Huntington’s disease. Neurology 53:1330–1332PubMedGoogle Scholar
  9. 9.
    Rubinsztein DC, Leggo J, Chiano M, Dodge A, Norbury G, Rosser E, Craufurd D (1997) Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci U S A 94:3872–3876CrossRefPubMedGoogle Scholar
  10. 10.
    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 87:493–506PubMedGoogle Scholar
  11. 11.
    Bates GP, Murphy KPSJ (2002) Mouse models of Huntington′s disease. In: Huntington’s disease, 3rd edn. Oxford University Press, Oxford, pp 387–428Google Scholar
  12. 12.
    Van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ (2000) Delaying the onset of Huntington’s in mice. Nature 404:721–722CrossRefPubMedGoogle Scholar
  13. 13.
    Van Dellen A, Deacon R, York D, Blakemore C, Hannan AJ (2001) Anterior cingulate cortical transplantation in transgenic Huntington’s disease mice. Brain Res Bull 56:313–318CrossRefPubMedGoogle Scholar
  14. 14.
    Hockly E, Cordery PM, Woodman B, Mahal A, Dellen A van, Blakemore C, Lewis CM, Hannan AJ, Bates GP (2002) Environmental enrichment slows disease progression in R6/2 Huntington’s disease mice. Ann Neurol 51:235–242CrossRefPubMedGoogle Scholar
  15. 15.
    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 U S A 97:8093–8097CrossRefPubMedGoogle Scholar
  16. 16.
    Burright EN, Clark HB, Servadio A, Matilla T, Feddersen RM, Yunis WS, Duvick LA, Zoghbi HY, Orr HT (1995) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82:937–948PubMedGoogle Scholar
  17. 17.
    Schilling G, Wood JD, Duan K, Slunt HH, Gonzales V, Yamada M, Cooper JK, Margolis RL, Jenkins NA, Copeland NG, Takahashi H, Tsuji S, Price DL, Borchelt DR, Ross CA (1999) Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA. Neuron 24:275–286PubMedGoogle Scholar
  18. 18.
    Abel A, Walcott J, Woods J, Duda J, Merry DE (2001) Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet 10:107–116CrossRefPubMedGoogle Scholar
  19. 19.
    McManamny P, Chy HS, Finkelstein DI, Craythorn RG, Crack PJ, Kola I, Cheema SS, Horne MK Wreford NG, O’Bryan MK, De Kretser DM, Morrison JR (2002) A mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 11:2103–2111CrossRefPubMedGoogle Scholar
  20. 20.
    Garden GA, Libby RT, Fu YH, Kinoshita Y, Huang J, Possin DE, Smith AC, Martinez RA, Fine GC, Grote SK, Ware CB, Einum DD, Morrison RS, Ptacek LJ, Sopher BL, La Spada AR (2002) Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. J Neurosci 22:4897–4905PubMedGoogle Scholar
  21. 21.
    Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A (1995) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet 11:155–163PubMedGoogle Scholar
  22. 22.
    Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35:76–83PubMedGoogle Scholar
  23. 23.
    Ordway JM, Tallaksen-Greene S, Gutekunst CA, Bernstein EM, Cearley JA, Wiener HW, Dure LS, Lindsey R, Hersch SM, Jope RS, Albin RL, Detloff PJ (1997) Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell 91:753–763PubMedGoogle Scholar
  24. 24.
    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 90:537–548PubMedGoogle Scholar
  25. 25.
    Sugars KL, Rubinsztein DC (2003) Transcriptional abnormalities in Huntington disease. Trends Genet 19:233–238CrossRefPubMedGoogle Scholar
  26. 26.
    Hollenbach B, Scherzinger E, Schweiger K, Lurz R, Lehrach H, Wanker EE (1999) Aggregation of truncated GST-HD exon 1 fusion proteins containing normal range and expanded glutamine repeats. Philos Trans R Soc Lond B Biol Sci 354:991–994CrossRefPubMedGoogle Scholar
  27. 27.
    Sittler A, Walter S, Wedemeyer N, Hasenbank R, Scherzinger E, Eickhoff H, Bates GP, Lehrach H, Wanker EE (1998) SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol Cell 2:427–436PubMedGoogle Scholar
  28. 28.
    Carmichael J, Chatellier J, Woolfson A, Milstein C, Fersht AR, Rubinsztein DC (2000) Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington’s disease. Proc Natl Acad Sci U S A 97:9701–9705CrossRefPubMedGoogle Scholar
  29. 29.
    Dedeoglu A, Ferrante RJ, Andreassen OA, Dillmann WH, Beal MF (2002) Mice overexpressing 70-kDa heat shock protein show increased resistance to malonate and 3-nitropropionic acid. Exp Neurol 176:262–265CrossRefPubMedGoogle Scholar
  30. 30.
    Hansson O, Nylandsted J, Castilho RF, Leist M, Jaattela M, Brundin P (2003) Overexpression of heat shock protein 70 in R6/2 Huntington’s disease mice has only modest effects on disease progression. Brain Res 970:47–57CrossRefPubMedGoogle Scholar
  31. 31.
    Martindale D, Hackam A, Wieczorek A, Ellerby L, Wellington C, McCutcheon K, Singaraja R, Kazemi-Esfarjani P, Devon R, Kim SU, Bredesen DE, Tufaro F, Hayden MR (1998) Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet 18:150–154PubMedGoogle Scholar
  32. 32.
    Kim M, Lee HS, LaForet G, McIntyre C, Martin EJ, Chang P, Kim TW, Williams M, Reddy PH, Tagle D, Boyce FM, Won L, Heller A, Aronin N, DiFiglia M (1999) Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J Neurosci 19:964–973PubMedGoogle Scholar
  33. 33.
    Li SH, Lam S, Cheng AL, Li XJ (2000) Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. Hum Mol Genet 9:2859–2867CrossRefPubMedGoogle Scholar
  34. 34.
    Luthi-Carter R, Strand A, Peters NL, Solano SM, Hollingsworth ZR, Menon AS, Frey AS, Spektor BS, Penney EB, Schilling G, Ross CA, Borchelt DR, Tapscott SJ, Young AB, Cha JH, Olson JM (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9:1259–1271Google Scholar
  35. 35.
    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 11:1911–1926CrossRefPubMedGoogle Scholar
  36. 36.
    Luthi-Carter R, Strand AD, Hanson SA, Kooperberg C, Schilling G, La Spada AR, Merry DE, Young AB, Ross CA, Borchelt DR, Olson JM (2002) Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington’s disease mouse models reveal context-independent effects. Hum Mol Genet 11:1927–1937CrossRefPubMedGoogle Scholar
  37. 37.
    Chan EY, Luthi-Carter R, Strand A, Solano SM, Hanson SA, DeJohn MM, Kooperberg C, Chase KO, DiFiglia M, Young AB, Leavitt BR, Cha JH, Aronin N, Hayden MR, Olson JM (2002) Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington’s disease. Hum Mol Genet 11:1939–1951CrossRefPubMedGoogle Scholar
  38. 38.
    Sipione S, Rigamonti D, Valenza M, Zuccato C, Conti L, Pritchard J, Kooperberg C, Olson JM, Cattaneo E (2002) Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum Mol Genet 11:1953–1965CrossRefPubMedGoogle Scholar
  39. 39.
    Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743CrossRefPubMedGoogle Scholar
  40. 40.
    Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PA, Steffan JS, Marsh JL, Thompson LM, Lewis CM, Marks PA, Bates GP (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci USA 100:2041–2046CrossRefPubMedGoogle Scholar
  41. 41.
    Cha JH, Kosinski CM, Kerner JA, Alsdorf SA, Mangiarini L, Davies SW, Penney JB, Bates GP, Young AB (1998) Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. Proc Natl Acad Sci U S A 95:6480–6485PubMedGoogle Scholar
  42. 42.
    Cha JH, Frey AS, Alsdorf SA, Kerner JA, Kosinski CM, Mangiarini L, Penney JB, Davies SW, Bates GP, Young AB (1999) Altered neurotransmitter receptor expression in transgenic mouse models of Huntington’s disease. Philos Trans R Soc Lond B Biol Sci 354:981–989CrossRefGoogle Scholar
  43. 43.
    Van Dellen A, Welch J, Dixon RM, Cordery P, Styles P, York D, Blakemore C, Hannan AJ (2000) N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington’s disease mice. Neuroreport 11:3751–3757PubMedGoogle Scholar
  44. 44.
    Cha JH (2000) Transcriptional dysregulation in Huntington’s disease. Trends Neurosci 23:387–392CrossRefPubMedGoogle Scholar
  45. 45.
    Bibb JA, Yan Z, Svenningsson P, Snyder GL, Pieribone VA, Horiuchi A, Nairn AC, Messer A, Greengard P (2000) Severe deficiencies in dopamine signaling in presymptomatic Huntington’s disease mice. Proc Natl Acad Sci U S A 97:6809–6814CrossRefPubMedGoogle Scholar
  46. 46.
    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 MF (1999) Enhanced sensitivity to N-methyl-d-aspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J Neurosci Res 58:515–532CrossRefPubMedGoogle Scholar
  47. 47.
    Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR, Raymond LA (2002) Increased sensitivity to N-methyl-d-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron 33:849–860PubMedGoogle Scholar
  48. 48.
    Murphy KP, Carter RJ, Lione LA, Mangiarini L, Mahal A, Bates GP, Dunnett SB, Morton AJ (2000) Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington’s disease mutation. J Neurosci 20:5115–5123PubMedGoogle Scholar
  49. 49.
    Usdin MT, Shelbourne PF, Myers RM, Madison DV (1999) Impaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Hum Mol Genet 8:839–846CrossRefPubMedGoogle Scholar
  50. 50.
    Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, Smith DJ, Bissada N, McCutcheon K, Nasir J, Jamot L, Li XJ, 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 23:181–192PubMedGoogle Scholar
  51. 51.
    Mazarakis N, Cybulska-Kosowicz A, Grote H, Dellen A van, Kossut M, Blakemore C, Hannan AJ (2003) Experience-dependent cortical plasticity and sensory discrimination learning deficits in presymptomatic Huntington’s disease mice (abstract). IBRO World Congress Neuroscience Abstracts 1327Google Scholar
  52. 52.
    Laforet GA, Sapp E, Chase K, McIntyre C, Boyce FM, Campbell M, Cadigan BA, Warzecki L, Tagle DA, Reddy PH, Cepeda C, Calvert CR, Jokel ES, Klapstein GJ, Ariano MA, Levine MS, DiFiglia M, Aronin N (2001) Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. J Neurosci 21:9112–9123PubMedGoogle Scholar
  53. 53.
    Macdonald V, Halliday G (2002) Pyramidal cell loss in motor cortices in Huntington’s disease. Neurobiol Dis 10:378–386CrossRefPubMedGoogle Scholar
  54. 54.
    Cepeda C, Hurst RS, Calvert CR, Hernandez-Echeagaray E, Nguyen OK, Jocoy E, Christian LJ, Ariano MA, Levine MS (2003) Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease. J Neurosci 23:961–969PubMedGoogle Scholar
  55. 55.
    Suen PC, Wu K, Levine ES, Mount HT, Xu JL, Lin SY, Black IB (1997) Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-d-aspartate receptor subunit 1. Proc Natl Acad Sci U S A 94:8191–8195CrossRefPubMedGoogle Scholar
  56. 56.
    Ferrer I, Goutan E, Marin C, Rey MJ, Ribalta T (2000) Brain-derived neurotrophic factor in Huntington disease. Brain Res 866:257–261CrossRefPubMedGoogle Scholar
  57. 57.
    Spires TL, Varshney N, Grote H, Dellen A van, Blakemore C, Hannan AJ (2002) Effects of environmental enrichment on disease symptoms, gene expression and protein aggregation in Huntington′s disease mice (abstract). Soc Neurosci Abstracts 28:388.13Google Scholar
  58. 58.
    Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293:493–498PubMedGoogle Scholar
  59. 59.
    Li H, Li SH, Yu ZX, Shelbourne P, Li XJ (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington’s disease mice. J Neurosci 1:8473–8484Google Scholar
  60. 60.
    Hickey MA, Chesselet MF (2003) Apoptosis in Huntington’s disease. Prog Neuropsychopharmacol Biol Psychiatry 27:255–265CrossRefPubMedGoogle Scholar
  61. 61.
    Butterworth NJ, Williams L, Bullock JY, Love DR, Faull RL, Dragunow M (1998) Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington’s disease striatum. Neuroscience 87:49–53Google Scholar
  62. 62.
    Volkmar FR, Greenough WT (1972) Rearing complexity affects branching of dendrites in the visual cortex of the rat. Science 176:1145–1147Google Scholar
  63. 63.
    Sharp PE, McNaughton BL, Barnes CA (1985) Enhancement of hippocampal field potentials in rats exposed to a novel, complex environment. Brain Res 339:361–365CrossRefPubMedGoogle Scholar
  64. 64.
    Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386:493–495PubMedGoogle Scholar
  65. 65.
    Van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270CrossRefPubMedGoogle Scholar
  66. 66.
    Van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nature Rev Neurosci 1:191–198CrossRefGoogle Scholar
  67. 67.
    Armstrong RJ, Barker RA (2001) Neurodegeneration: a failure of neuroregeneration? Lancet 358:1174–1176CrossRefPubMedGoogle Scholar
  68. 68.
    Rampon C, Jiang CH, Dong H, Tang YP, Lockhart DJ, Schultz PG, Tsien JZ, Hu Y (2000) Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci U S A 97:12880–12884CrossRefPubMedGoogle Scholar
  69. 69.
    Pham TM, Ickes B, Albeck D, Soderstrom S, Granholm AC, Mohammed AH (1999) Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year. Neuroscience 94:279–286CrossRefPubMedGoogle Scholar
  70. 70.
    Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RG, Morrison JH, O’Dell TJ, Grant SG (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396:433–439PubMedGoogle Scholar
  71. 71.
    Foster TC, Gagne J, Massicotte G (1996) Mechanism of altered synaptic strength due to experience: relation to long-term potentiation. Brain Res 736:243–250PubMedGoogle Scholar
  72. 72.
    Young D, Lawlor PA, Leone P, Dragunow M, During MJ (1999) Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 5:448–453CrossRefPubMedGoogle Scholar
  73. 73.
    Nihei K, Kowall NW (1992) Neurofilament and neural cell adhesion molecule immunocytochemistry of Huntington’s disease striatum. Ann Neurol 31:59–63PubMedGoogle Scholar
  74. 74.
    Tukamoto T, Nukina N, Ide K, Kanazawa I (1997) Huntington’s disease gene product, huntingtin, associates with microtubules in vitro. Brain Res Mol Brain Res 51:8–14CrossRefPubMedGoogle Scholar
  75. 75.
    Singhrao SK, Thomas P, Wood JD, MacMillan JC, Neal JW, Harper PS, Jones AL (1998) Huntingtin protein colocalizes with lesions of neurodegenerative diseases: an investigation in Huntington’s, Alzheimer’s, and Pick’s diseases. Exp Neurol 150:213–222CrossRefPubMedGoogle Scholar
  76. 76.
    Muchowski PJ, Ning K, D’Souza-Schorey C, Fields S (2002) Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment. Proc Natl Acad Sci U S A 99:727–732CrossRefPubMedGoogle Scholar
  77. 77.
    Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP (2003) Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci USA 100:2911–2916CrossRefPubMedGoogle Scholar
  78. 78.
    Clifford JJ, Drago J, Natoli AL, Wong JY, Kinsella A, Waddington JL, Vaddadi KS (2002) Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease. Neuroscience 109:81–88CrossRefPubMedGoogle Scholar
  79. 79.
    Georgiou N, Bradshaw JL, Chiu E, Tudor A, O’Gorman L, Phillips JG (1999) Differential clinical and motor control function in a pair of monozygotic twins with Huntington’s disease. Mov Disord 14:320–325CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.University Laboratory of PhysiologyUniversity of OxfordOxfordUK
  2. 2.Howard Florey InstituteUniversity of MelbourneAustralia

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