Transcriptional Dysregulation in Huntington’s Disease

  • James Duce
  • Cathy Hartog
  • Lyn Elliston
  • James W. Neal
  • Louise F. B. Nicholson
  • A. Lesley Jones
Part of the Advances in Behavioral Biology book series (ABBI, volume 52)


Huntington’s disease (HD) is an autosomal dominant neurodegeneration which is associated with an expanded CAG repeat in a large gene on chromosome 4p. The protein product of the gene, huntingtin, thus contains an expanded glutamine tract close to its N-terminus. Although the genetic lesion was defined in 1993 (Huntington’s disease collaborative research group, 1993) neither the normal nor pathological function of huntingtin has been defined. Despite the widespread expression of the HD gene in effectively all cell types examined (DiFiglia et al., 1995; Ferrante et al., 1997; Gutekunst et al., 1995; Kosinski et al., 1997) the initial pathology of HD is restricted and specific populations of neurons in the striatum are vulnerable (Vonsattel et al., 1985). The neurons which die first are the medium spiny projection neurons in the caudate and putamen, and those most vulnerable are the enkephalin-containing, dopamine D2 expressing neurons projecting to the globus pallidus pars externa (GPe) (Albin et al., 1990; 1992). The death of neurons is accompanied by extensive reactive gliosis and, at later stages of disease, atrophy occurs in other regions of the basal ganglia and elsewhere with brain weight at death significantly reduced compared to controls (Vonsattel et al., 1985).


Polyglutamine Tract Control Cortex Nuclear Receptor Corepressor Disease Collaborative Research Group Transcriptional Repressor Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albin, R. L., Qin, Y., Young, A. B., Penney, J. B., & Chesselet, M. F., 1991, Preproenkephalin messenger RNA-containing neurons in striatum of patients with symptomatic and presymptomatic Huntington’s disease: an in situ hybridization studyAnn.Neurol. 30: 542–549.PubMedCrossRefGoogle Scholar
  2. Albin, R. L., Reiner, A., Anderson, K. D., Dure, t. S., Handelin, B., Balfour, R., Whetsell, W. O., Penney, J. B. and Young, A. B., 1992. Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease.Annals of Neurology 31425–30.PubMedCrossRefGoogle Scholar
  3. Albin, R., Young, A. and Penney, J.. 1990, Abnormalities of striatal projections neurons and N-methyl-D-aspartate in presymptomatic Huntington’s Disease.New England Journal of Medicine 3221293–1298.PubMedCrossRefGoogle Scholar
  4. Alland, L., Muhle, R., Hou, H., Jr., Potes, J., Chin, L., Schreiber-Agus, N., & DePinho, R. A. 1997, Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repressionNature 387: 49–55.PubMedCrossRefGoogle Scholar
  5. Arzberger, T., Krampfl, K., Leimgruber, S., & Weindl, A., 1997, Changes of NMDA receptor subunit (NRI, NR2B) and glutamate transporter (GLTI) mRNA expression in Huntington’s disease--an in situhybridization studyJ. Neuropathol.Exp.Neurol. 56: 440–454.PubMedCrossRefGoogle Scholar
  6. Augood, S. J., Faull, R. L., & Emson, P. C., 1997, Dopamine DI and D2 receptor gene expression in the striatum in Huntington’s diseaseAnn.Neurol. 42: 215–221.PubMedCrossRefGoogle Scholar
  7. Augood, S. J., Faull, R. L., Love, D. R., & Emson, P. C., 1996, Reduction in enkephalin and substance P messenger RNA in the striatum of early grade Huntington’s disease: a detailed cellular in situ hybridizationstudy. Neuroscience 72: 1023–1036.CrossRefGoogle Scholar
  8. Bibb, J. A., Yan, Z., Svenningsson, P., Snyder, G. L., Pieribone, V. A., Horiuchi, A.. Nairn, A. C., Messer, A., & Greengard, P., 2000, Severe deficiencies in dopamine signaling in presymptomatic Huntington’s disease miceProc.Natl.Acad.Sci.U.S.A 97: 6809–6814.PubMedCrossRefGoogle Scholar
  9. Boutell, J. M., Thomas, P., Neal, J. W., Weston, V. J., Duce, J., Harper, P. S., & Jones, A. L. 1999, Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtinHum. Mol.Genet. 8: 1647–1655.PubMedCrossRefGoogle Scholar
  10. Cha, J. H., Frey, A. S., Alsdorf, S. A., Kerner, J. A., Kosinski, C. M., Mangiarini, L., Penney, J. B., Jr., Davies, S. W., Bates, G. P., & Young, A. B., 1999, Altered neurotransmitter receptor expression in transgenic mouse models of Huntington’s diseasePhilos.Trans.R.Soc.Lond.B.Biol.Sci. 354:981–989.PubMedCrossRefGoogle Scholar
  11. Cha, J. H., Kosinski, C. M., Kerner, J. A., Alsdorf, S. A., Mangiarini, L., Davies, S. W., Penney, J. B., Bates, G. P., & Young, A. B., 1998, Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease geneProc.Natl.Acad.Sci.U.S.A. 95: 6480–6485.PubMedCrossRefGoogle Scholar
  12. Cohen, R.N., Wondisford F.E., Hollenberg, A.N., 1998, Two separate N-CoR (nuclear receptor corepressor) interaction domains mediate corepressor action on thyroid hormone response elementsMol Endocrinol. 37:1567–1581CrossRefGoogle Scholar
  13. Davies, S. W., Turmaine, M., Cozens, B. A., DiFiglia, M., Sharp, A. H., Ross, C. A., Scherzinger, E., Wanker, E. E., Mangiarini, L., & Bates, G. P. 1997, Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutationCell 90: 537–548.PubMedCrossRefGoogle Scholar
  14. Denovan-Wright, E. M. & Robertson, H. A., 2000, Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington’s disease miceNeuroscience 98: 705–713.PubMedCrossRefGoogle Scholar
  15. DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P., & Aronin, N. 1997, Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brainScience 277: 1990–1993.PubMedCrossRefGoogle Scholar
  16. DiFiglia, M., Sapp, E., Chase, K., Schwarz, C., Meloni, A., Young, C., Martin, E., Vonsattel, J. P., Carraway, R., & Reeves, S. A., 1995, Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neuronsNeuron 14: 1075–1081.PubMedCrossRefGoogle Scholar
  17. Ferrante, R. J., Gutekunst, C. A., Persichetti, F., McNeil, S. M., Kowall, N. W., Gusella, J. F., MacDonald, M. E., Beal, M. F. and Hersch, S. M., (1997) Heterogeneous topographic and cellular distribution of huntingtin expression in the normal human neostriatum.Journal of Neuroscience 173052–63.PubMedGoogle Scholar
  18. Gutekunst, C. A., Levey, A. I., Heilman, C. J., Whaley, W. L., Yi, H., Nash, N. R., Rees, H. D., Madden, J. J., & Hersch, S. M., 1995, Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodiesProc.Natl.AcadSci.USA. 92: 8710–8714.CrossRefGoogle Scholar
  19. Hassig, C. A. & Schreiber, S. L. 1997, Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACsCurr.Opin.Chem.Biol. 1: 300–308.PubMedCrossRefGoogle Scholar
  20. Holbert, S., Denghien, I., Kiechle, T., Rosenblatt, A., Wellington, C., Hayden, M. R., Margolis, R. L., Ross, C. A., Dausset, J., Ferrante, R. J., & Neri, C., 2001, The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologie and genetic evidence for a role in Huntington’s disease pathogenesisProc.Natl.Acad.Sci. USA 98: 1811–1816.PubMedCrossRefGoogle Scholar
  21. Huntington’s Disease Collaborative Research Group, 1993, A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomesCell 72: 971–983.CrossRefGoogle Scholar
  22. Jepsen, K., Hermanson, O., Onami, T. M., Gleiberman, A. S., Lunyak, V., McEvilly, R. J., Kurokawa, R., Kumar, V., Liu, F., Seto, E., Hedrick, S. M., Mandel, G., Glass, C. K., Rose, D. W., & Rosenfeld, M. G., 2000, Combinatorial roles of the nuclear receptor corepressor in transcription and developmentCell 102: 753–763.PubMedCrossRefGoogle Scholar
  23. Kosinski, C. M., Cha, J. H., Young, A. B., Persichetti, F., MacDonald, M., Gusella, J. F., Penney, J. B., Jr., & Standaert, D. G., 1997, Huntingtin immunoreactivity in the rat neostriatum: differential accumulation in projection and interneuronsExp.Neurol. 144: 239–247.PubMedCrossRefGoogle Scholar
  24. Lawrence, A. D., Weeks, R. A., Brooks, D. J., Andrews, T. C., Watkins, L. H., Harding, A. E., Robbins, T. W., & Sahakian, B. J., 1998, The relationship between striatal dopamine receptor binding and cognitive performance in Huntington’s diseaseBrain 121: 1343–1355.PubMedCrossRefGoogle Scholar
  25. Levine, M. S., Klapstein, G. J., Koppel, A., Gruen, E., Cepeda, C., Vargas, M. E., Jokel, E. S., Carpenter, E. M., Zanjani, H., Hurst, R. S., Efstratiadis, A., Zeitlin, S., & Chesselet, M. F., 1999, Enhanced sensitivity to Nmethyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington’s diseaseJ.Neurosci.Res. 58: 515–532.PubMedCrossRefGoogle Scholar
  26. Luthi-Carter, R., Strand, A., Peters, N. L., Solano, S. M., Hollingsworth, Z. R., Menon, A. S., Frey, A. S., Spektor, B. S., Penney, E. B., Schilling, G., Ross, C. A., Borchelt, D. R., Tapscott, S. J., Young, A. B., Cha, J. H., & Olson, J. M., 2000, Decreased expression of striatal signaling genes in a mouse model of Huntington’s diseaseHum.Mol Genet. 9: 1259–1271.PubMedCrossRefGoogle Scholar
  27. Menalled, L., Zanjani, H., MacKenzie, L., Koppel, A., Carpenter, E., Zeitlin, S., & Chesselet, M. F., 2000, Decrease in striatal enkephalin mRNA in mouse models of Huntington’s diseaseExp Neurol. 162: 328–342.PubMedCrossRefGoogle Scholar
  28. Nucifora, F. C, Jr., Sasaki, M., Peters, M. F., Huang, H., Cooper, J. K., Yamada, M., Takahashi, H., Tsuji, S., Troncoso, J., Dawson, V. L., Dawson, T. M., & Ross, C. A., 2001, Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicityScience 291: 2423–2428.PubMedCrossRefGoogle Scholar
  29. Richfield, E. K. & Herkenham, M., 1994, Selective vulnerability in Huntington’s disease: preferential loss of cannabinoid receptors in lateral globus pallidusAnn.Neurol. 36: 577–584.PubMedCrossRefGoogle Scholar
  30. Richfield, E. K., Maguire-Zeiss, K. A., Cox, C., Gilmore, J., & Voorn, P., 1995, Reduced expression of preproenkephalin in striatal neurons from Huntington’s disease patientsAnn.Neurol.37: 335–343.PubMedCrossRefGoogle Scholar
  31. Shimohata, T, Nakajima, T., Yamada, M.. Uchida, C.,Onodera, O., Naruse, al.2000, Expanded polyglutamine stretches interact with TAFI1130, interfering with CREB-dependent transcription. Nat. Genet.26: 1985–1989Google Scholar
  32. Sieradzan, K. A., Mechan, A. O., Jones, L., Wanker, E. E., Nukina,N., & Mann, D. M., 1999, Huntington’s disease intranuclear inclusions contain truncated, ubiquitinated huntingtin proteinExp.Neurol. 156: 92–99.PubMedCrossRefGoogle Scholar
  33. Steffan, J. S., Bodai, L., Palios, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y. Z., Greenwald, M., Kurokawa, R., Housman, D. E., Jackson, G. R., Marsh, J. L., & Thompson, L. M., 2001, Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in DrosophilaNature413: 739–743.PubMedCrossRefGoogle Scholar
  34. Vonsattel, J. P., Myers, R. H., Stevens, T. J., Ferrante, R. J., Bird, E. D. and Richardson, E. P., 1985, Neuropathological classification of Huntington’s disease.J Neuropathol Exp Neurol 44559–77.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • James Duce
    • 1
  • Cathy Hartog
    • 1
  • Lyn Elliston
    • 1
  • James W. Neal
    • 2
  • Louise F. B. Nicholson
    • 3
  • A. Lesley Jones
    • 1
  1. 1.Institute of Medical GeneticsCardiffUK
  2. 2.Department of PathologyUniversity of Wales College of MedicineCardiffUK
  3. 3.Department of Anatomy with RadiologyUniversity of AucklandNew Zealand

Personalised recommendations