Mechanistic Insights into the Polyglutamine Ataxias

  • Victor M. Miller
  • Henry L. Paulson
Part of the Protein Reviews book series (PRON, volume 6)


Several hypotheses have been advanced in order to explain the molecular mechanisms by which expanded polyglutamine (polyQ) triggers neurodegeneration. In this chapter, we discuss the experimental evidence supporting the leading hypotheses in the field. In particular, we focus on the mechanisms by which abnormal protein folding, oligomerization, and aggregation may impair neuronal function and survival in the dominant spinocerebellar ataxias (SCAs) caused by polyQ expansion.


Axonal Transport Spinocerebellar Ataxia Hereditary Spastic Paraplegia Disease Protein Autosomal Dominant Cerebellar Ataxia 
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  1. Alavi, A., Dann, R., Chawluk, J., Alavi, J., Kushner, M., and Reivich, M. (1986). Positron emission tomography imaging of regional cerebral glucose metabolism. Semin Nucl Med 16: 2–34.PubMedCrossRefGoogle Scholar
  2. Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., and Finkbeiner, S. (2004). Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805–810.PubMedCrossRefGoogle Scholar
  3. Beal, M. F., Brouillet, E., Jenkins, B. G., Ferrante, R. J., Kowall, N. W., Miller, J. M., Storey, E., Srivastava, R., Rosen, B. R., and Hyman, B. T. (1993). Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 13: 4181–4192.PubMedGoogle Scholar
  4. Bence, N. F., Sampat, R. M., and Kopito, R. R. (2001). Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292: 1552–1555.PubMedCrossRefGoogle Scholar
  5. Berke, S. J., and Paulson, H. L. (2003). Protein aggregation and the ubiquitin proteasome pathway: gaining the UPPer hand on neurodegeneration. Curr Opin Genet Dev 13: 253–261.PubMedCrossRefGoogle Scholar
  6. Boutell, J. M., Thomas, P., Neal, J. W., Weston, V. J., Duce, J., Harper, P. S., and Jones, A. L. (1999). Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin. Hum Mol Genet 8: 1647–1655.PubMedCrossRefGoogle Scholar
  7. Bowman, A. B., Yoo, S. Y., Dantuma, N. P., and Zoghbi, H. Y. (2005). Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet 14: 679–691.PubMedCrossRefGoogle Scholar
  8. Browne, S. E., Bowling, A. C., MacGarvey, U., Baik, M. J., Berger, S. C., Muqit, M. M., 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.PubMedCrossRefGoogle Scholar
  9. Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y. S., Myers, R. M., Roses, A. D., Vance, J. M., and Strittmatter, W. J. (1996). Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat Med 2: 347–350.PubMedCrossRefGoogle Scholar
  10. Burnett, B. G., and Pittman, R. N. (2005). The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci USA 102: 4330–4335.PubMedCrossRefGoogle Scholar
  11. Chai, Y., Wu, L., Griffin, J. D., and Paulson, H. L. (2001). The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease. J Biol Chem 276: 44889–44897.PubMedCrossRefGoogle Scholar
  12. Chai, Y., Shao, J., Miller, V. M., Williams, A., and Paulson, H. L. (2002). Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. Proc Natl Acad Sci USA 99: 9310–9315.PubMedCrossRefGoogle Scholar
  13. Chan, H. Y., Warrick, J. M., Gray-Board, G. L., Paulson, H. L., and Bonini, N. M. (2000). Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9: 2811–2820.PubMedCrossRefGoogle Scholar
  14. Chen, S., Berthelier, V., Yang, W., and Wetzel, R. (2001). Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J Mol Biol 311: 173–182.PubMedCrossRefGoogle Scholar
  15. Chen, S., Ferrone, F. A., and Wetzel, R. (2002). Huntington’s disease age-of-onset linked to polyglutamine aggregation nucleation. Proc Natl Acad Sci USA 99: 11884–11889.PubMedCrossRefGoogle Scholar
  16. Cummings, C. J., Mancini, M. A., Antalffy, B., DeFranco, D. B., Orr, H. T., and Zoghbi, H. Y. (1998). Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19: 148–154.PubMedCrossRefGoogle Scholar
  17. Cummings, C. J., Sun, Y., Opal, P., Antalffy, B., Mestril, R., Orr, H. T., Dillmann, W. H., and Zoghbi, H. Y. (2001). Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 10: 1511–1518.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. Ferrante, R. J., Andreassen, O. A., Jenkins, B. G., 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.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. Fletcher, C. F., Lutz, C. M., O’Sullivan, T. N., Shaughnessy, J. D., Jr., Hawkes, R., Frankel, W. N., Copeland, N. G., and Jenkins, N. A. (1996). Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 87: 607–617.PubMedCrossRefGoogle Scholar
  22. Gerber, H. P., Seipel, K., Georgiev, O., Hofferer, M., Hug, M., Rusconi, S., and Schaffner, W. (1994). Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 263: 808–811.PubMedCrossRefGoogle Scholar
  23. Goto, S., Takahashi, R., Kumiyama, A. A., Radak, Z., Hayashi, T., Takenouchi, M., and Abe, R. (2001). Implications of protein degradation in aging. Ann N Y Acad Sci 928: 54–64.PubMedCrossRefGoogle Scholar
  24. Gu, M., Gash, M. T., Mann, V. M., Javoy-Agid, F., Cooper, J. M., and Schapira, A. H. (1996). Mitochondrial defect in Huntington’s disease caudate nucleus. Ann Neurol 39: 385–389.PubMedCrossRefGoogle Scholar
  25. Gunawardena, S., and Goldstein, L. S. (2005). Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways. Arch Neurol 62: 46–51.PubMedCrossRefGoogle Scholar
  26. Gunawardena, S., Her, L. S., Brusch, R. G., Laymon, R. A., Niesman, I. R., Gordesky-Gold, B., Sintasath, L., Bonini, N. M., and Goldstein, L. S. (2003). Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40: 25–40.PubMedCrossRefGoogle Scholar
  27. Hansson, O., Nylandsted, J., Castilho, R. F., Leist, M., Jaattela, M., and 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: 47–57.PubMedCrossRefGoogle Scholar
  28. Hartl, F. U., and Hayer-Hartl, M. (2002). Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295: 1852–1858.PubMedCrossRefGoogle Scholar
  29. Hay, D. G., Sathasivam, K., Tobaben, S., Stahl, B., Marber, M., Mestril, R., Mahal, A., Smith, D. L., Woodman, B., and Bates, G. P. (2004). Progressive decrease in chaperone protein levels in a mouse model of Huntington’s disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet 13: 1389–1405.PubMedCrossRefGoogle Scholar
  30. Helmlinger, D., Hardy, S., Sasorith, S., Klein, F., Robert, F., Weber, C., Miguet, L., Potier, N., Van-Dorsselaer, A., Wurtz, J. M., et al. (2004). Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 13: 1257–1265.PubMedCrossRefGoogle Scholar
  31. Hirakura, Y., Azimov, R., Azimova, R., and Kagan, B. L. (2000). Polyglutamine-induced ion channels: a possible mechanism for the neurotoxicity of Huntington and other CAG repeat diseases. J Neurosci Res 60: 490–494.PubMedCrossRefGoogle Scholar
  32. Hockly, E., Richon, V. M., Woodman, B., Smith, D. L., Zhou, X., Rosa, E., Sathasivam, K., Ghazi-Noori, S., Mahal, A., Lowden, P. A., et al. (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: 2041–2046.PubMedCrossRefGoogle Scholar
  33. Hughes, R. E., and Olson, J. M. (2001). Therapeutic opportunities in polyglutamine disease. Nat Med 7: 419–423.PubMedCrossRefGoogle Scholar
  34. Huntington Study Group. (2001). A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 57: 397–404.Google Scholar
  35. Ishikawa, K., Fujigasaki, H., Saegusa, H., Ohwada, K., Fujita, T., Iwamoto, H., Komatsuzaki, Y., Toru, S., Toriyama, H., Watanabe, M., et al. (1999). Abundant expression and cytoplasmic aggregations of [alpha]1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. Hum Mol Genet 8: 1185–1193.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., and Glabe, C. G. (2003). Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300: 486–489.PubMedCrossRefGoogle Scholar
  38. Kayed, R., Sokolov, Y., Edmonds, B., McIntire, T. M., Milton, S. C., Hall, J. E., and Glabe, C. G. (2004). Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 279: 46363–46366.PubMedCrossRefGoogle Scholar
  39. Klement, I. A., Skinner, P. J., Kaytor, M. D., Yi, H., Hersch, S. M., Clark, H. B., Zoghbi, H. Y., and Orr, H. T. (1998). Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95: 41–53.PubMedCrossRefGoogle Scholar
  40. Matsuyama, Z., Wakamori, M., Mori, Y., Kawakami, H., Nakamura, S., and Imoto, K. (1999). Direct alteration of the P/Q-type Ca2+ channel property by polyglutamine expansion in spinocerebellar ataxia 6. J Neurosci 19: RC14.PubMedGoogle Scholar
  41. McMahon, S. J., Pray-Grant, M. G., Schieltz, D., Yates, J. R., 3rd, and Grant, P. A. (2005). Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity. Proc Natl Acad Sci USA 102: 8478–8482.PubMedCrossRefGoogle Scholar
  42. Miller, V. M., Nelson, R. F., Gouvion, C. M., Williams, A., Rodriguez-Lebron, E., Harper, S. Q., Davidson, B. L., Rebagliati, M. R., and Paulson, H. L. (2005). CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. J Neurosci. 25(40): 9125–9161.CrossRefGoogle Scholar
  43. Monoi, H., Futaki, S., Kugimiya, S., Minakata, H., and Yoshihara, K. (2000). Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases. J Biophys 78: 2892–2899.CrossRefGoogle Scholar
  44. Nakamura, K., Jeong, S. Y., Uchihara, T., Anno, M., Nagashima, K., Nagashima, T., Ikeda, S., Tsuji, S., and Kanazawa, I. (2001). SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10: 1441–1448.PubMedCrossRefGoogle Scholar
  45. Nollen, E. A., Garcia, S. M., van Haaften, G., Kim, S., Chavez, A., Morimoto, R. I., and Plasterk, R. H. (2004). Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci USA 101: 6403–6408.PubMedCrossRefGoogle Scholar
  46. Panov, A. V., Gutekunst, C. A., Leavitt, B. R., Hayden, M. R., Burke, J. R., Strittmatter, W. J., and Greenamyre, J. T. (2002). Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5: 731–736.PubMedGoogle Scholar
  47. Paulson, H. L., Perez, M. K., Trottier, Y., Trojanowski, J. Q., Subramony, S. H., Das, S. S., Vig, P., Mandel, J. L., Fischbeck, K. H., and Pittman, R. N. (1997). Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19: 333–344.PubMedCrossRefGoogle Scholar
  48. Perez, M. K., Paulson, H. L., Pendse, S. J., Saionz, S. J., Bonini, N. M., and Pittman, R. N. (1998). Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 143: 1457–1470.PubMedCrossRefGoogle Scholar
  49. Reid, E., Kloos, M., Ashley-Koch, A., Hughes, L., Bevan, S., Svenson, I. K., Graham, F. L., Gaskell, P. C., Dearlove, A., Pericak-Vance, M. A., et al. (2002). A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 71: 1189–1194.PubMedCrossRefGoogle Scholar
  50. Scheel, H., Tomiuk, S., and Hofmann, K. (2003). Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics. Hum Mol Genet 12: 2845–2852.PubMedCrossRefGoogle Scholar
  51. Schols, L., Bauer, P., Schmidt, T., Schulte, T., and Riess, O. (2004). Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 3: 291–304.PubMedCrossRefGoogle Scholar
  52. Shimohata, T., Nakajima, T., Yamada, M., Uchida, C., Onodera, O., Naruse, S., Kimura, T., Koide, R., Nozaki, K., Sano, Y., et al. (2000). Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26: 29–36.PubMedCrossRefGoogle Scholar
  53. Steffan, J. S., Kazantsev, A., Spasic-Boskovic, O., Greenwald, M., Zhu, Y. Z., Gohler, H., Wanker, E. E., Bates, G. P., Housman, D. E., and Thompson, L. M. (2000). The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA 97: 6763–6768.PubMedCrossRefGoogle Scholar
  54. Steffan, J. S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y. Z., Greenwald, M., et al. (2001). Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739–743.PubMedCrossRefGoogle Scholar
  55. Stenoien, D. L., Mielke, M., and Mancini, M. A. (2002). Intranuclear ataxin1 inclusions contain both fast-and slow-exchanging components. Nat Cell Biol 4: 806–810.PubMedCrossRefGoogle Scholar
  56. Stokin, G. B., Lillo, C., Falzone, T. L., Brusch, R. G., Rockenstein, E., Mount, S. L., Raman, R., Davies, P., Masliah, E., Williams, D. S., and Goldstein, L. S. (2005). Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307: 1282–1288.PubMedCrossRefGoogle Scholar
  57. Sugars, K. L., and Rubinsztein, D. C. (2003). Transcriptional abnormalities in Huntington disease. Trends Genet 19: 233–238.PubMedCrossRefGoogle Scholar
  58. Szebenyi, G., Morfini, G. A., Babcock, A., Gould, M., Selkoe, K., Stenoien, D. L., Young, M., Faber, P. W., MacDonald, M. E., McPhaul, M. J., and Brady, S. T. (2003). Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40: 41–52.PubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. Taroni, F., and DiDonato, S. (2004). Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci 5: 641–655.PubMedCrossRefGoogle Scholar
  61. Taylor, J. P., Hardy, J., and Fischbeck, K. H. (2002). Toxic proteins in neurodegenerative disease. Science 296: 1991–1995.PubMedCrossRefGoogle Scholar
  62. Taylor, J. P., Taye, A. A., Campbell, C., Kazemi-Esfarjani, P., Fischbeck, K. H., and Min, K. T. (2003). Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev 17: 1463–1468.PubMedCrossRefGoogle Scholar
  63. Venkatraman, P., Wetzel, R., Tanaka, M., Nukina, N., and Goldberg, A. L. (2004). Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell 14: 95–104.PubMedCrossRefGoogle Scholar
  64. Verbessem, P., Lemiere, J., Eijnde, B. O., Swinnen, S., Vanhees, L., Van Leemputte, M., Hespel, P., and Dom, R. (2003). Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology 61: 925–930.PubMedGoogle Scholar
  65. Warrick, J. M., Chan, H. Y., Gray-Board, G. L., Chai, Y., Paulson, H. L., and Bonini, N. M. (1999). Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23: 425–428.PubMedCrossRefGoogle Scholar
  66. Williamson, T. L., and Cleveland, D. W. (1999). Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 2: 50–56.PubMedCrossRefGoogle Scholar
  67. Willingham, S., Outeiro, T. F., DeVit, M. J., Lindquist, S. L., and Muchowski, P. J. (2003). Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science 302: 1769–1772.PubMedCrossRefGoogle Scholar
  68. Yang, Q., Hashizume, Y., Yoshida, M., Wang, Y., Goto, Y., Mitsuma, N., Ishikawa, K., and Mizusawa, H. (2000). Morphological Purkinje cell changes in spinocerebellar ataxia type 6. Acta Neuropathol (Berl) 100: 371–376.CrossRefGoogle Scholar
  69. Yang, W., Dunlap, J. R., Andrews, R. B., and Wetzel, R. (2002). Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum Mol Genet 11: 2905–2917.PubMedCrossRefGoogle Scholar
  70. Yoo, S. Y., Pennesi, M. E., Weeber, E. J., Xu, B., Atkinson, R., Chen, S., Armstrong, D. L., Wu, S. M., Sweatt, J. D., and Zoghbi, H. Y. (2003). SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 37: 383–401.PubMedCrossRefGoogle Scholar
  71. Zhao, C., Takita, J., Tanaka, Y., Setou, M., Nakagawa, T., Takeda, S., Yang, H. W., Terada, S., Nakata, T., Takei, Y., et al. (2001). Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105: 587–597.PubMedCrossRefGoogle Scholar
  72. Zhuchenko, O., Bailey, J., Bonnen, P., Ashizawa, T., Stockton, D. W., Amos, C., Dobyns, W. B., Subramony, S. H., Zoghbi, H. Y., and Lee, C. C. (1997). Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15: 62–69.PubMedCrossRefGoogle Scholar
  73. Zoghbi, H. Y., and Orr, H. T. (2000). Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23: 217–247.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Victor M. Miller
    • 1
  • Henry L. Paulson
    • 1
  1. 1.Department of NeurologyUniversity of Iowa College of MedicineIowa CityUSA

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