Skip to main content
SpringerLink
Log in

The Energetics of Huntington's Disease

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Huntington's disease (HD) is a hereditary neurodegenerative disorder that gradually robs sufferers of the ability to control movements and induces psychological and cognitive impairments. This devastating, lethal disease is one of several neurological disorders caused by trinucleotide expansions in affected genes, including spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy, and spinal bulbar muscular atrophy. HD symptoms are associated with region-specific neuronal loss within the central nervous system, but to date the mechanism of this selective cell death remains unknown. Strong evidence from studies in humans and animal models suggests the involvement of energy metabolism defects, which may contribute to excitotoxic processes, oxidative damage, and altered gene regulation. The development of transgenic mouse models expressing the human HD mutation has provided novel opportunities to explore events underlying selective neuronal death in HD, which has hitherto been impossible in humans. Here we discuss how animal models are redefining the role of energy metabolism in HD etiology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Vonsattel, J. P. G. and DiFiglia, M. 1998. Huntington disease. J. Neuropathol. Exp. Neurol. 57:369–384.

    PubMed  Google Scholar 

  2. Andrews, T. C., Weeks, R. A., Turjanski, N., Gunn, R. N., Watkins, L. H., Sahakian, B., Hodges, J. R., Rosser, A. E., Wood, N. W., and Brooks, D. J. 1999. Huntington's disease progression: PET and clinical observations. Brain 122:2353–2363.

    PubMed  Google Scholar 

  3. Beal, M. F., Ellison, D. W., Mazurek, M. F., Swartz, K. J., Malloy, J. R., Bird, E. D., and Martin, J. B. 1988. A detailed examination of substance P in pathologically graded cases of Huntington's disease. J. Neurol. Sci. 84:51–61.

    PubMed  Google Scholar 

  4. Albin, R. L., Reiner, A., Anderson, K. D., Penney, J. B., and Young, A. B. 1990. Striatal and nigral neuron subpopulations in rigid Huntington's disease: Implications for the functional anatomy of chorea and rigidity-akinesia. Ann. Neurol. 27:357–365.

    PubMed  Google Scholar 

  5. Kuwert, T., Lange, H. W., Langer, K.-J., Herzog, H., Aulich, A., and Feinendegen, L. E. 1990. Cortical and subcortical glucose consumption measured by PET in patients with Huntington's disease. Brain 113:1405–1423.

    PubMed  Google Scholar 

  6. The Huntington's Disease Collaborative Research Group. 1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosome. Cell 72:971–983.

    Google Scholar 

  7. MacDonald, M. E., Vonsattel, J.-P., Shrinidhi, J., Couropmitree, N. N., Cupples, L. A., Bird, E. D., Gusella, J. F., Myers, R. H. 1999. Evidence for the GluR6 gene associated with younger onset age of Huntington's disease. Neurology 53:1330–1332.

    PubMed  Google Scholar 

  8. Butterworth, N. J., Williams, L., Bullock, J. Y., Love, D. R., Faull, R. L., and Dragunow, M. 1998. Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum. Neuroscience 87:49–53.

    PubMed  Google Scholar 

  9. Ross, C. A. 1995. When less is more: Pathogenesis in glutamine repeat neurodegenerative diseases. Neuron 15:493–496.

    PubMed  Google Scholar 

  10. DiFiglia, M., Sapp, E., Chase, K., Schwarz, C., Meloni, A., Young, C., Martin, E., Vonsattel, J.-P., Carraway, R., Reeves, S. A., Boyce, F. M., and Aronin, N. 1995. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14:1075–1081.

    PubMed  Google Scholar 

  11. White, J. K., Auerbach, W., Duyao, M. P., Vonsattel, J.-P., Gusella, J. F., Joyner, A. L., and MacDonald, M. E. 1997. Huntingtin function is required for mouse brain development and is not impaired by the Huntington's disease CAG expansion mutation. Nat. Genet. 17:404–410.

    PubMed  Google Scholar 

  12. Rigamonti, D., Bauer, J. H., De-Fraja, C., Conti, L., Sipione, S., Sciorati, C., Clementi, E., Hackam, A., Hayden, M. R., Li, Y., Cooper, J. K., Ross, C. A., Govoni, S., Vincenz, C., and Cattaneo, E. 2000. Wild-type huntingtin protects from apoptosis upstream of caspase-3. J. Neurosci. 20:3705–3713.

    PubMed  Google Scholar 

  13. Hoffner, G., Kahlem, P., and Dijan, P. 2002. Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: Relevance to Huntington's disease. J. Cell Sci. 115:941–948.

    PubMed  Google Scholar 

  14. Duyao, M. P., Auerbach, A. B., Persichetti, F., Barnes, G. T., McNeil, S. M., Ge, P., Vonsattel, J.-P., Gusella, J. F., Joyner, A. L., and MacDonald, M. E. 1995. Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269:407–410.

    PubMed  Google Scholar 

  15. Auerbach, W., Hurlbert, M. S., Hilditch-Maguire, P., Wadghiri, Y. Z., Wheeler, V. C., Cohen, S. I., Joyner, A. L., MacDonald, M. E., and Turnbull, D. H. 2001. The HD mutation causes progressive lethal neurological disease in mice expressing reduced levels of huntingtin. Hum. Mol. Genet. 10:2515–2523.

    PubMed  Google Scholar 

  16. Sharp, N. H., Love, S. J., Schilling, G., Li, S.-H., Li, X.-J., Bao, J., Wagster, M. V., Kotzuk, J. A., Steiner, J. P., Lo, A., Hedreen, J., Sisodia, S., Snyder, S. H., Dawson, T. M., Ryugo, D. K., and Ross, C. A. 1995. Widespread expression of the Hunt-ington's disease gene (IT-15) protein product. Neuron 14:1065–1074.

    PubMed  Google Scholar 

  17. Sapp, E., Schwarz, C., Chase, K., Bhide, P. G., Young, A. B., Penney, J., Vonsattel, J. P., Aronin, N., and DiFiglia, M. 1997. Huntingtin localization in brains of normal and Huntington's disease patients. Ann. Neurol. 42:604–612.

    PubMed  Google Scholar 

  18. 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. J. Neurosci. 17:3052–3063.

    PubMed  Google Scholar 

  19. Fusco, F. R., Chen, Q., Lamoreaux, W. J., Figueredo-Cardenas, G., Jiao, Y., Coffman, J. A., Surmeier, D. J., Honig, M. G., Carlock, L. R., and Reiner, A. 1999. Cellular localization of huntingtin in striatal and cortical neurons in rats: Lack of correlation with neuronal vulnerability in Huntington's disease. J. Neurosci. 19:1189–1202.

    PubMed  Google Scholar 

  20. Meade, C. A., Deng, Y. P., Fusco, F. R., Del Mar, N., Hersch, S., Goldowitz, D., and Reiner, A. 2002. Cellular localization and development of neuronal intranuclear inclusions in striatal and cortical neurons in R6/2 transgenic mice. J. Comp. Neurol. 449:241–269.

    PubMed  Google Scholar 

  21. Lunkes, A., Lindenberg, K. S., Ben-Haiem, L., Weber, C., Devys, D., Landwehrmeyer, G. B., Mandel, J.-L., and Trottier, Y. 2002. Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol. Cell 10:259–269.

    PubMed  Google Scholar 

  22. Davies, S. W., Turmaine, M., Cozens, B., DiFiglia, M., Sharp, A., Ross, C. A., Scherzinger, E., Wanker, E. E., Mangiarini, L., and Bates, G. 1997. Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548.

    PubMed  Google Scholar 

  23. DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J.-P., and Aronin, N. 1997. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993.

    PubMed  Google Scholar 

  24. Hodgson, J. G., Agopyan, N., Gutekunst, C.-A., Leavitt, B. R., LePiane, F., Singaraja, R., Smith, D. J., Bissada, N., McCutchoon, K., Nasir, J., Jamot, L., Li, X.-J., Rosemond, E., Roder, J. C., Phillips, A. G., Rubin, E. M., Hersch, S. M., and Hayden, M. R. 1999. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23:1–20.

    PubMed  Google Scholar 

  25. Schilling, G., Bacher, M. W., Sharp, A. H., Jinnah, H. A., Duyao, K., Kotzuk, J. A., Slunt, H. H., Ratovitski, T., Cooper, J. A., Jenkins, N. A., et al. 1999. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 8:397–407.

    PubMed  Google Scholar 

  26. Wheeler, V. C., White, J. K., Gutekunst, C. A., Vrbanac, V., Weaver, M., Li, X. J., Li, S. H., Yi, H., Vonsattel, J. P., Gusella, J. F., Hersch, S., Auerbach, W., Joyner, A. L., and MacDonald, M. E. 2000. Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum. Mol. Genet. 9:503–513.

    PubMed  Google Scholar 

  27. Saudou, F., Finkbeiner, S., Devys, D., and Greenberg, M. E. 1998. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66.

    PubMed  Google Scholar 

  28. Rubinsztein, D. C. 2002. Lessons from animal models of Huntington's disease. Trends Gen. 18:202–209.

    Google Scholar 

  29. Kim, M., Lee, H. S., LaForet, G., McIntyre, C., Martin, E. J., Chang, P., Kim, T. W., Williams, M., Reddy, P. H., Tagle, D., Boyee, F. M., Won, L., Heller, A., Aronin, N., and DiFiglia, M. 1999. Mutant huntingtin expression in clonal striatal cells: Dissociation of inclusion formation and neuronal survival by caspase inhibition. J. Neurosci. 19:964–73.

    PubMed  Google Scholar 

  30. Peters, M. F., Nucifora, F. C. Jr., Kushi, J., Seaman, H. C., Cooper, J. K., Herring, W. J., Dawson, V. L., Dawson, T. M., and Ross, C. A. 1999. Nuclear targeting of mutant Huntingtin increases toxicity. Mol. Cell Neurosci. 14:121–128.

    PubMed  Google Scholar 

  31. Martin-Aparicio, E., Avila, J., and Lucas, J. J. 2002. Nuclear localization of N-terminal mutant huntingtin is cell cycle dependent. Eur. J. Neurosci. 16:355–359.

    PubMed  Google Scholar 

  32. Cooper, A. J. L., Sheu, K.-F. R., Burke, J. R., Onodera, O., Strittmatter, W. J., Roses, A. D., and Blass, J. P. 1997. Transglutaminase-catalyzed inactivation of glyceraldehyde 3-phosphate dehydrogenase and ά-ketoglutarate dehydrogenase complex by polyglutamine domains of pathological length. Proc. Natl. Acad. Sci. USA 94:12604–12609.

    PubMed  Google Scholar 

  33. Cooper, A. J., Sheu, K. F., Burke, J. R., Strittmatter, W. J., Gentile, V., Peluso, G., and Blass, J. P. 1999. Pathogenesis of inclusion bodies in (CAG)n/Qn-expansion diseases with special reference to the role of tissue transglutaminase and to selective vulnerability. J. Neurochem. 72:889–899.

    PubMed  Google Scholar 

  34. Hickey, M. A. and Chesselet, M. F. 2003. Apoptosis in Huntington's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 27:255–265.

    PubMed  Google Scholar 

  35. Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y.-S., Myers, R. M., Roses, A. D., Vance, V. M., and Strittmatter, W. J. 1996. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat. Med. 2:347–350.

    PubMed  Google Scholar 

  36. Aronin, N., Kim, M., Laforet, G., and DiFiglia, M. 1999. Are there multiple pathways in the pathogenesis of Huntington's disease? Phil. Trans. R. Soc. Lond. 354:995–1003.

    Google Scholar 

  37. Steffan, J. S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y. Z., Greenwald, M., Kurokawa, R., Housman, D. E., Jackson, C. R., Marsh, J. L., and Thompson, L. M. 2001. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743.

    PubMed  Google Scholar 

  38. Dunah, A. W., Jeong, H., Griffin, A., Kim, Y. M., Standaert, D. G., Hersch, S. M., Mouradian, M. M., Young, A. B., Tanese, N., and Krainc, D. 2002. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 296:2238–2243.

    PubMed  Google Scholar 

  39. O'Brien, C. F., Miller, C., Goldblatt, D., Welle, S., Forbes, G., Lipinski, B., Panzik, J., Peck, R., Plumb, S., Oakes, D., Kurlan, R., and Shoulson, I. 1990. Extraneural metabolism in early Huntington's disease. Ann. Neurol. 28:300–301.

    Google Scholar 

  40. Djousse, L., Knowlton, B., Cupples, L. A., Marder, K., Shoulson, I., and Myers, R. H. 2002. Weight loss in early stage of Huntington's disease. Neurology 59:1325–1330.

    PubMed  Google Scholar 

  41. Andrews, T. C. and Brooks, D. J. 1998. Advances in the understanding of early Huntington's disease using the functional imaging techniques of PET and SPET. Mol. Med. Today 4:532–539.

    PubMed  Google Scholar 

  42. Kuhl, D. E., Markham, C. H., Metter, E. J., Riege, W. H., Phelps, M. E., and Mazziotta, J. C. 1985. Local cerebral glucose utilization in symptomatic and presymptomatic Huntington's disease. Res. Publ. Assoc. Res. Nerv. Men. Dis. 63:199–209.

    Google Scholar 

  43. Berent, S., Giordani, B., Lehtinen, S., Markel, D., Penney, J. B., Buchtel, H. A., Starosta Rubinstein, S., Hichwa, R., and Young, A. B. 1988. Positron emission tomographic scan investigations of Huntington's disease: Cerebral metabolic correlates. Ann. Neurol. 23:541–546.

    PubMed  Google Scholar 

  44. Grafton, S. T., Mazziotta, J. C., Pahl, J. J., St George-Hyslop, P., Haines, J. L., Gusella, J., Hoffman, J. M., Baxter, L. R., and Phelps, M. E. 1992. Serial changes of cerebral glucose metabolism and caudate size in persons at risk for Huntington's disease. Arch. Neurol. 49:1161–1167.

    PubMed  Google Scholar 

  45. Kuwert, T., Lange, H. W., Boecker, H., Titz, H., Herzog, H., Aulich, A., Wang, B. C., Nayak, U., and Feinendegen, L. E. 1993. Striatal glucose consumption in chorea-free subjects at risk of Huntington's disease. J. Neurol. 241:31–36.

    PubMed  Google Scholar 

  46. Antonini, A., Leenders, K. L., Spiegel, R., Meier, D., Vontobel, P., Weigell-Weber, M., Sanchez-Pernaute, R., de Yebenez, J. G., Boesiger, P., Weindl, A., and Maguire, R. P. 1996. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients. Brain 119:2085–2095.

    PubMed  Google Scholar 

  47. Feigin, A., Leenders, K. L., Moeller, J. R., Missimer, J., Kuenig, G., Spetsieris, P., Antonini, A., and Eidelberg, D. 2001. Metabolic network abnormalities in early Huntington's disease: An [(18)F] FDG PET study. J. Nucl. Med. 42:1591–1595.

    PubMed  Google Scholar 

  48. Jenkins, B. G., Koroshetz, W., Beal, M. F., and Rosen, B. 1993. Evidence for an energy metabolism defect in Huntington's disease using localized proton spectroscopy. Neurology 43:2689–2695.

    PubMed  Google Scholar 

  49. Jenkins, B. G., Rosas, H. D., Chen, Y. C., Makabe, T., Myers, R., MacDonald, M., Rosen, B. R., Beal, M. F., and Koroshetz, W. J. 1998. 1H NMR spectroscopy studies of Huntington's disease: Correlations with CAG repeat numbers. Neurology 50:1357–1365.

    PubMed  Google Scholar 

  50. Koroshetz, W. J., Jenkins, B. G., Rosen, B. R., and Beal, M. F. 1997. Energy metabolism defects in Huntington's disease and possible therapy with coenzyme Q10. Ann. Neurol. 41:160–165.

    PubMed  Google Scholar 

  51. Nicoli, F., Vion-Dury, J., Maloteaux, J. M., Delwaide, C., Confort-Gouny, S., Sciaky, M., and Cozzone, P. J. 1993. CSF and serum metabolic profile of patients with Huntington's chorea: A study by high resolution proton NMR spectroscopy and HPLC. Neurosci. Lett. 154:47–51.

    PubMed  Google Scholar 

  52. Lodi, R., Schapira, A. H., Manners, D., Styles, P., Wood, N. W., Taylor, D. J., and Warner, T. T. 2000. Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy. Ann. Neurol. 48:72–76.

    PubMed  Google Scholar 

  53. Butterworth, J., Yates, C. M., and Reynolds, G. P. 1985. Distribution of phosphate-activated glutaminase, succinic dehydrogenase, pyruvate dehydrogenase, and γ-glutamyl transpeptidase in post-mortem brain from Huntington's disease and agonal cases. J. Neurol. Sci. 67:161–171.

    PubMed  Google Scholar 

  54. Browne, S. E., Bowling, A. C., MacGarvey, U., Baik, M. J., Berger, S. C., Muqit, M. M. K., Bird, E. D., and Beal, M. F. 1997. Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia. Ann. Neurol. 41:646–653.

    PubMed  Google Scholar 

  55. Gu, M., Gash, M. T., Mann, V. M., Javoy-Agid, F., Cooper, J. M., and Schapira, A. H. V. 1996. Mitochondrial defect in Huntington's disease caudate nucleus. Ann. Neurol. 39:385–389.

    PubMed  Google Scholar 

  56. Parker, W. D. Jr., Boyson, S. J., Luder, A. S., and Parks, J. K. 1990. Evidence for a defect in NADH:ubiquinone oxidoreductase (complex I) in Huntington's disease. Neurology 40:1231–1234.

    PubMed  Google Scholar 

  57. Arenas, J., Campos, Y., Ribacoba, R., Martin, M. A., Rubio, J. C., Ablanedo, P., and Cabello, A. 1998. Complex I defect in muscle from patients with Huntington's disease. Ann. Neurol. 43:397–400.

    PubMed  Google Scholar 

  58. Guidetti, P., Charles, V., Chen, E. Y., Reddy, P. H., Kordower, J. H., Whetsell, W. O. Jr., Schwarcz, R., and Tagle, D. A. 2001. Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production. Exp. Neurol. 169:340–50.

    PubMed  Google Scholar 

  59. Tabrizi, S. J., Cleeter, M. W., Xuereb, J., Taanman, J. W., Cooper, J. M., and Schapira, A. H. 1999. Biochemical abnormalities and excitotoxicity in Huntington's disease brain. Ann. Neurol. 45:25–32.

    PubMed  Google Scholar 

  60. Mastrogiacomo, F., LaMarche, J., Dozic, S., Lindsay, G., Bettendorff, L., Robitaille, Y., Schut, L., and Kish, S. J. 1996. Immunoreactive levels of alpha-ketoglutarate dehydrogenase subunits in Friedreich's ataxia and spinocerebellar ataxia type 1. Neurodegen. 5:27–33.

    Google Scholar 

  61. Matsuishi, T., Sakai, T., Naito, E., Nagamitsu, S., Kuroda, Y., Iwashita, H., and Kato, H. 1996. Elevated cerebrospinal fluid lactate/pyruvate ratio in Machado-Joseph disease. Acta Neurol. Scand. 93:72–75.

    PubMed  Google Scholar 

  62. Mazzola, J. L. and Sirover, M. A. 2001. Reduction of glyceraldehyde-3-phosphate dehydrogenase activity in Alzheimer's disease and in Huntington's disease fibroblasts. J. Neurochem. 76:442–449.

    PubMed  Google Scholar 

  63. Mazzola, J. L. and Sirover, M. A. 2002. Alteration of nuclear glyceraldehyde-3-phosphate dehydrogenase structure in Huntington's disease fibroblasts. Brain Res. Mol. Brain Res. 100:95–101.

    PubMed  Google Scholar 

  64. Senatorov, V. V., Charles, V., Reddy, P. H., Tagle, D. A., and Chuang, D. M. 2003. Overexpression and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase in a transgenic mouse model of Huntington's disease. Mol. Cell Neurosci. 22:285–297.

    PubMed  Google Scholar 

  65. Ludolph, A. C., He, F., Spencer, P. S., Hammerstad, J., and Sabri, M. 1990. 3-Nitropropionic acid: Exogenous animal neurotoxin and possible human striatal toxin. Can. J. Neurol. Sci. 18:492–498.

    Google Scholar 

  66. Browne, S. E. and Beal, M. F. 2002. Toxin-induced mitochondrial dysfunction. Int. Rev. Neurobiol. 53:243–279.

    PubMed  Google Scholar 

  67. Brouillet, E., Hantraye, P., Ferrante, R. J., Dolan, R., Leroy-Willig, A., Kowall, N. W., and Beal, M. F. 1995. Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc. Natl. Acad. Sci. USA 92:7105–7109.

    PubMed  Google Scholar 

  68. Brouillet, E., Guyot, M. C., Mittoux, V., Altairac, S., Conde, F., Palfi, S., and Hantraye, P. 1998. Partial inhibition of brain succinate dehydrogenase by 3-nitropropionic acid is sufficient to initiate striatal degeneration in rat. J. Neurochem. 70:794–805.

    PubMed  Google Scholar 

  69. Matthews, R. T., Yang, L., Jenkins, B. J., Ferrante, R. J., Rosen, B. R., Kaddurah-Daouk, R., and Beal, M. F. 1998. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease. J. Neurosci. 18:156–163.

    PubMed  Google Scholar 

  70. Faber, P. W., Alter, J. R., MacDonald, M. E., and Hart, A. C. 1999. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc. Natl. Acad. Sci. USA 96:179–184.

    PubMed  Google Scholar 

  71. von Horsten, S., Schmitt, I., Nguyen, H. P., Holzmann, C., Schmidt, T., et al. 2003. Transgenic rat model of Huntington's disease. Hum. Mol. Genet. 12:617–24.

    PubMed  Google Scholar 

  72. Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S. W., and Bates, G. 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.

    PubMed  Google Scholar 

  73. Laforet, G. A., Sapp, E., Chase, K., McIntyre, C., Boyce, F. M., Campbell, M., Cadigan, B. A., Warzeeki, L., Tagle, D. A., Reddy, P. H., Cepeda, C., Calvert, C. R., Jokel, E. S., Klapstein, G. J., Ariano, M. A., Levine, M. S., DiFiglia, M., and 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: 9112–9123.

    PubMed  Google Scholar 

  74. Yamamoto, A., Lucas, J. J., and Hen, R. 2000. Reversal of neuropathy and motor dysfunction in a conditional model of Huntington's disease. Cell 101:57–66.

    PubMed  Google Scholar 

  75. Reddy, P. H., Williams, M., Charles, V., Garrett, L., Pike-Buchanan, L., Whetsell, W. O. Jr., Miller, G., and Tagle, D. A. 1998. Behavioural abnormalities and selective neuonal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat. Genet. 20:198–202.

    PubMed  Google Scholar 

  76. 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., and 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.

    PubMed  Google Scholar 

  77. Lin, C. H., Tallaksen-Greene, S., Chien, W. M., Cearley, J. A., Jackson, W. S., Crouse, A. B., Ren, S., Li, X. J., Albin, R. L., and Detloff, P. J. 2001. Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum. Mol. Genet. 10:137–144.

    PubMed  Google Scholar 

  78. Shelbourne, P. F., Killeen, N., Hevner, R. F., Johnston, H. M., Tecott, L., Lewandoski, M., Ennis, M., Ramirez, L., Li, Z., Iannicola, C., Littman, D. R., and Myers, R. M. 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.

    PubMed  Google Scholar 

  79. Ishiguru, 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., and 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.

    PubMed  Google Scholar 

  80. Yu, Z.-X., Li, S.-H., Evans, J., Pillarisetti, A., Li, H., and Li, X.-J. 2003. Mutant huntingtin causes context-dependent neurodegeneration in mice with Huntington's disease. J. Neurosci. 23:2193–2202.

    PubMed  Google Scholar 

  81. Browne, S. E., Wheeler, V., White, J. K., Fuller, S. W., MacDonald, M., and Beal, M. F. 1999. Dose-dependent alterations in local cerebral glucose use associated with the huntingtin mutation in Hdh CAG knock-in transgenic mice. Soc. Neurosci. Abstr. 25:218.11.

    Google Scholar 

  82. Gregorio, J., DiMauro, J.-P. P., Narr, S., Fuller, S. W., and Browne, S. E. 2002. Cerebral metabolism defects in HD: Glucose utilization abnormalities in multiple HD mouse models. Soc. Neurosci. Abstr. 28:195.10

    Google Scholar 

  83. Wheeler, V. C., Gutekunst, C. A., Vrbanac, V., Lebel, L. A., Schilling, G., Hersch, S., Friedlander, R. M., Gusella, J. F., Vonsattel, J. P., Borchelt, D. R., MacDonald, M. E. 2002. Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice. Hum. Mol. Genet. 11:633–640.

    PubMed  Google Scholar 

  84. Panov, A. V., Gutekunst, C. A., Lelavitt, B. R., Hayden, M. R., Burke, J. R., Strittmatter, W. J., and Greenamyre, J. T. 2002. Early mitochonrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat. Neurosci. 5:731–736.

    PubMed  Google Scholar 

  85. Tabrizi, S. J., Workman, J., Hart, P. E., Mangiarini, L., Mahal, A., Bates, G., Cooper, J. M., and Schapira, A. H. 2000. Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann. Neurol. 47:80–86.

    PubMed  Google Scholar 

  86. Panov, A. V., Burke, J. R., Strittmatter, W. J., and Greenamyre, J. T. 2003. In vitro effects of polyglutamine tracts on Ca2+-dependent depolarization of rat and human mitochondria: Relevance to Huntington's disease. Arch. Biochem. Biophys. 410:1–6.

    PubMed  Google Scholar 

  87. Bresolin, N., Bet, L., Binda, A., Moggio, M., Comi, G., Nador, F., Ferrante, C., Carenzi, A., and Searlato, G. 1988. Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Q10. Neurology 38:892–899.

    PubMed  Google Scholar 

  88. Ihara, Y., Namba, R., Kuroda, S., Sato, T., and Shirabe, T. 1989. Mitochondrial encephalomyopathy (MELAS): Pathological study and successful therapy with coenzyme Q10 and idebenone. J. Neurol. Sci. 90:263–271.

    PubMed  Google Scholar 

  89. Beal, M. F., Henshaw, D. R., Jenkins, B. G., Rosen, B. R., and Schulz, J. B. 1994. Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann. Neurol. 36:882–888.

    PubMed  Google Scholar 

  90. Schulz, J. B., Matthews, R. T., Henshaw, D. R., and Beal, M. F. 1996. Neuroprotective strategies for treatment of lesions produced by mitochondrial toxins: Implications for neurodegenerative diseases. Neurosci. 71:1043–1048.

    Google Scholar 

  91. Schilling, G., Coonfield, M. L., Ross, C. A., and Borchelt, D. R., 2001. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model. Neurosci. Lett. 315:149–153.

    PubMed  Google Scholar 

  92. Ferrante, R. J., Andreassen, O. A., Dedeoglu, A., Ferrante, K. L., Jenkins, B. G., Hersch, S. M., and Beal, M. F. 2002. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J. Neurosci. 22:1592–1599.

    PubMed  Google Scholar 

  93. Huntington Study Group. 2001. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology 57:375–376.

    Google Scholar 

  94. Wyss, M. and Schulze, A. 2002. Health implications of creatine: Can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience 112:243–260.

    PubMed  Google Scholar 

  95. Tarnopolsky, M. A. and Beal, M. F. 2001. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann. Neurol. 49:561–574.

    PubMed  Google Scholar 

  96. Ferrante, R. J., Andreassen, O. A., Dedeoglu, A., Kuemmerle, S., Kubilus, J. K., Kaddurah-Daouk, R., Hersch, S. M., and Beal, M. F. 2000. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J. Neurosci. 20:4389–4397.

    PubMed  Google Scholar 

  97. Andreassen, O. A., Dedeoglu, A., Ferrante, R. J., Jenkins, B. J., Ferrante, K. L., Thomas, M., Friedlich, A., Browne, S. E., Schilling, G., Borchelt, D. R., Hersch, S. M., Ross, C. A., Beal, M. F. 2001. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease. Neurobiol. Dis. 8:479–491.

    PubMed  Google Scholar 

  98. Kaemmerer, W. F., Rodrigues, C. M., Steer, C. J., and Low, W. C. 2001. Creatine-supplemented diet extends Purkinje cell survival in spinocerebellar ataxia type 1 transgenic mice but does not prevent the ataxic phenotype. Neuroscience 103:713–724.

    PubMed  Google Scholar 

  99. Andreassen, O. A., Ferrante, R. J., Huang, H. M., Dedeoglu, A., Park, L., Ferrante, K. L., Kwon, J., Borchelt, D. R., Ross, C. A., Gibson, G. E., and Beal, M. F. 2001. Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington's disease. Ann. Neurol. 50:112–117.

    PubMed  Google Scholar 

  100. Albin, R. L. and Greenamyre, J. T. 1992. Alternative excitotoxic hypotheses. Neurology 42:733–738.

    PubMed  Google Scholar 

  101. Browne, S. E., Ferrante, R. J., and Beal, M. F. 1999. Oxidative stress in Huntington's disease. Brain Pathol. 9:147–163.

    PubMed  Google Scholar 

  102. Novelli, A., Reilly, J. A., Lysko, P. G., and Henneberry, R. C. 1988. Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res. 451:205–212.

    PubMed  Google Scholar 

  103. Henneberry, R. L., Novelli, A., Cox, J. A., and Lysko, P. G. 1989. Neurotoxicity at the N-methyl-D-aspartate receptor in energy-compromised neurons: An hypothesis for cell death in aging and disease. Ann. NY Acad. Sci. 568:225–233.

    PubMed  Google Scholar 

  104. Zeevalk, G. D. and Nicklas, W. J. 1991. Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition. J. Pharm. Exp. Ther. 257:870–878.

    Google Scholar 

  105. Dure, L. S. 4th, Young A. B., and Penney, J. B. 1991. Excitatory amino acid binding sites in the caudate nucleus and frontal cortex of Huntington's disease. Ann. Neurol. 30:785–793.

    PubMed  Google Scholar 

  106. Albin, R. L., Young, A. B., Penney, J. B., Handelin, B., Balfour, R., Anderson, K. D., Markel, D. S., Tourtellotte, W. W., and Reiner, A. 1990. Abnormalities of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington's disease. N. Engl. J. Med. 322:1293–1298.

    PubMed  Google Scholar 

  107. Ferrante, R. J., Kowall, N. W., Cipolloni, P. B., Storey, E., and Beal, M. F. 1993. Excitotoxin lesions in primates as a model for Huntington's disease: Histopathologic and neurochemical characterization. Exp. Neurol. 119:46–71.

    PubMed  Google Scholar 

  108. Wullner, U., Young, A. B., Penney, J. B., and Beal, M. F. 1994. 3-Nitropropionic acid toxicity in the striatum. J. Neurochem. 63:1772–1781.

    PubMed  Google Scholar 

  109. Zeron, M. M., Hansson, O., Chen, N., Wellington, C. L., Leavitt, B. R., Brundin, P., Hayden, M. R., and Raymond, L. A. 2002. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33:849–860.

    PubMed  Google Scholar 

  110. Petersen, A., Chase, K., Puschban, Z., DiFiglia, M., Brundin, P., and Aronin, N. 2002. Maintenance of susceptibility to neurodegeneration following intrastriatal injections of quinolinic acid in a new transgenic mouse model of Huntington's disease. Exp. Neurol. 175:297–300.

    PubMed  Google Scholar 

  111. Hansson, O., Castilho, R. F., Korhonen, L., Lindholm, D., Bates, G. P., and Brundin, P. 2001. 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.

    PubMed  Google Scholar 

  112. Hickey, M. A. and Morton, A. J. 2000. Mice transgenic for the Huntington's disease mutation are resistant to chronic 3-nitopropionic acid-induced striatal toxicity. J. Neurochem. 75:2163–2171.

    PubMed  Google Scholar 

  113. Petersen, A., Hansson, O., Puschban, Z., Sapp, E., Romero, N., Castilho, R. F., Sulzer, D., Rice, M., DiFiglia, M., Przedborski, S., and Brundin, P. 2001. 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.

    PubMed  Google Scholar 

  114. Cepeda, C., Hurst, R. S., Calvert, C. R., Hernandez-Echeagaray, E., Nguyen, O. K., Jocoy, E., Christian, L. J., Ariano, M. A., and Levine, M. S. 2003. Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington's disease. J. Neurosci. 23:961–996.

    PubMed  Google Scholar 

  115. Schiefer, J., Landwehrmeyer, G. B., Luesse, H. G., Sprunken, A., Puls, C., Milkereit, A., Milkereit, E., and Kosinski, C. M. 2002. Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease. Mov. Disord. 17:748–757.

    PubMed  Google Scholar 

  116. Polidori, M. C., Mecocci, P., Browne, S. E., Senin, U., and Beal, M. F. 1999. Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex. Neurosci. Lett. 272:53–56.

    PubMed  Google Scholar 

  117. Bogdanov, M. B., Andreassen, O. A., Dedeoglu, A., Ferrante, R. J., Beal, M. F. 2001. Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease. J. Neurochem. 79:1246–1249.

    PubMed  Google Scholar 

  118. Calabrese, V., Scapagnini, G., Giuffrida-Stella, A. M., Bates, T. E., and Clark, J. B. 2001. Mitochondrial involvement in brain function and dysfunction: Relevance to aging, neurodegenerative disorders and longevity. Neurochem. Res. 26:739–764.

    PubMed  Google Scholar 

  119. Brown, G. C. and Borutaite, V. 2001. Nitric oxide, mitochondria, and cell death. IUBMB Life 52:189–195.

    PubMed  Google Scholar 

  120. Lafon-Cazal, M., Culcasi, M., Gaven, F., Pietri, S., and Bockaert, J. 1993. Nitric oxide, superoxide and peroxynitrite: Putative mediators of NMDA-induced cell death in cerebellar granule cells. Neuropharmacology 32:1259–1266.

    PubMed  Google Scholar 

  121. Dykens, J. A. 1994. Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated Ca2+ and Na+: Implications for neurodegeneration. J. Neurochem. 63:584–591.

    PubMed  Google Scholar 

  122. Bolanos, J. P., Heales, S. J. R., Land, J. M., and Clark, J. B. 1995. Effect of peroxynitrite on the mitochondrial respiratory chain: Differential susceptibility of neurones and astrocytes in primary culture. J. Neurochem. 64:1965–1972.

    PubMed  Google Scholar 

  123. Schulz, J. B., Henshaw, D. R., MacGarvey, U., and Beal, M. F. 1996. Involvement of oxidative stress in 3-nitropropionic acid neurotoxicity. Neurochem. Intl. 29:167–171.

    Google Scholar 

  124. Schulz, J. B., Henshaw, D. R., Siweck, D., Jenkins, B. G., Ferrante, R. J., Cipolloni, P. B., Kowall, N. W., Rosen, B. R., Beal, M. F. 1995. Involvement of free radicals in excitotoxicity in vivo. J. Neurochem. 64:2239–2247.

    PubMed  Google Scholar 

  125. Gines, S., Seong, I. S., Fossale, E., Ivanova, E., Trettel, F., Gusella, J. F., Wheeler, V. C., Persichetti, F., and MacDonald, M. E. 2003. Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Hum. Mol. Genet. 12:497–508.

    PubMed  Google Scholar 

  126. Cramer, H., Warter, J. M., and Renaud, B. 1984. Analysis of neurotransmitter metabolites and adenosine 3′ 5′-monophosphate in the CSF of patients with extrapyramidal motor disorders. Adv. Neurol. 40:431–435.

    PubMed  Google Scholar 

  127. Wyttenbach, A., Swartz, J., Kita, H., Thykjaer, T., Carmichael, J., Bradley, J., Brown, R., Maxwell, M., Schapira, A., Orntoft, T. F., et al. 2001. Polyglutamine expansions cause decreased CRE-mediated transcription and early gene expression changes prior to cell death in an inducible cell model of Huntington's disease. Hum. Mol. Genet. 10:1829–1845.

    PubMed  Google Scholar 

  128. Ferrer, I., Goutan, E., Marin, C., Rey, M. J., and Ribalta, T. 2000. Brain-derived neurotrophic factor in Huntington disease. Brain Res. 866:257–261.

    PubMed  Google Scholar 

  129. Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V., Hayden, M. R. et al. 2001. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 293:493–498.

    PubMed  Google Scholar 

  130. 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 disease. Hum. Mol. Genet. 9:1259–1271.

    PubMed  Google Scholar 

  131. Luthi-Carter, R., Hanson, S. A., Strand, A. D., Bergstrom, D. A., Chun, W., Peters, N. L., Woods, A. M., Chan, E. Y., Kooperberg, C., Krainc, D., Young A. B., Tapscott, S. J., and Olson, J. M. 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.

    PubMed  Google Scholar 

  132. Cheng, B. and Mattson, M. P. 1994. NT-3 and BDNF protect CNS neurons against metabolic excitotoxic insults. Brain Res. 640:56–67.

    PubMed  Google Scholar 

  133. Duan, W. and Guo, Z. 2001. Brain-derived neurotrophic factor mediates an excitoprotective effect of dietary restriction in mice. J. Neurochem. 76:619–626.

    PubMed  Google Scholar 

  134. Bemelmans, A. P., Horellou, P., Pradier, L., Brunet, I., Colin, P., and Mallet, J. 1999. Brain derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer. Hum. Gene Ther. 10:2987–2997.

    PubMed  Google Scholar 

  135. Perez-Navarro, E., Canudas, A. M., Akerund, P., Alberch, J., and Arenas, E. 2000. Brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 prevent the death of striatal projection neurons in a rodent model of Huntington's disease. J. Neurochem. 75:2190–2199.

    PubMed  Google Scholar 

  136. Duan, W., Guo, Z., Jiang, H., Ware, M., Li, X. J., and Mattson, M. P. 2003. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc. Natl. Acad. Sci. USA 100:2911–2916.

    PubMed  Google Scholar 

  137. Luthi-Carter, R., Strand, A. D., Hanson, S. A., Kooperberg, C., Schilling, G., LaSpada, A. R., Merry, D. E., Young, A. B., Ross, C. A., Borchelt, D. R., Olson, J. M. 2002. Polyglutamine and transcription: Gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects. Hum. Mol. Genet. 11:1927–1937.

    PubMed  Google Scholar 

  138. Chan, E. Y., Luthi-Carter, R., Strand, A., Solano, S. M., Hanson, S. A., DeJohn, M. M., Kooperberg, C., Chase, K. O., DiFigliia, M., Young, A. B., Leavitt, B. R., Cha, J. H., Aronin, N., Hayden, M. R., and Olson, J. M. 2002. Increased huntingtin protein length reduces the number of polyglutamine-induced gene expression changes in mouse models of Huntington's disease. Hum. Mol. Genet. 11:1939–1951.

    PubMed  Google Scholar 

  139. Sipione, S., Rigamonti, D., Valenza, M., Zuccato, C., Conti, L., Pritchard, J., Kooperberg, C., Olson, J. M., and Cattaneo, E. 2002. Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. Hum. Mol. Genet. 11:1953–1965.

    PubMed  Google Scholar 

  140. Ravikumar, B., Stewart, A., Kita, H., Kato, K., Duden, R., and Rubinsztein, D. C. 2003. Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy. Hum. Mol. Genet. 12:985–994.

    PubMed  Google Scholar 

  141. Ravikumar, B., Duden, R., and Rubinsztein, D. C. 2002. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11:1107–1117.

    PubMed  Google Scholar 

  142. Kita, H., Carmichael, J., Swartz, J., Muro, S., Wyttenbach, A., Matsubara, K., Rubinsztein, D. C., and Kato, K. 2002. Modulation of polyglutamine-induced cell death by genes identified by expression profiling. Hum. Mol. Genet. 11:2279–2287.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York

    Susan E. Browne & M. Flint Beal

Authors
  1. Susan E. Browne
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Flint Beal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan E. Browne.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Browne, S.E., Beal, M.F. The Energetics of Huntington's Disease. Neurochem Res 29, 531–546 (2004). https://doi.org/10.1023/B:NERE.0000014824.04728.dd

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:NERE.0000014824.04728.dd

Search

Navigation