Molecules and Cells

, Volume 27, Issue 6, pp 621–627 | Cite as

Molecular pathogenesis of spinocerebellar ataxia type 1 disease



Spinocerebellar ataxia type 1 (SCA1) is an autosomal-dominant neurodegenerative disorder characterized by ataxia and progressive motor deterioration. SCA1 is associated with an elongated polyglutamine tract in ataxin-1, the SCA1 gene product. As summarized in this review, recent studies have clarified the molecular mechanisms of SCA1 pathogenesis and provided direction for future therapeutic approaches. The nucleus is the subcellular site where misfolded mutant ataxin-1 acts to cause SCA1 disease in the cerebellum. The role of these nuclear aggregates is the subject of intensive study. Additional proteins have been identified, whose conformational alterations occurring through interactions with the polyglutamine tract itself or non-polyglutamine regions in ataxin-1 are the cause of SCA-1 cytotoxicity. Therapeutic hope comes from the observations concerning the reduction of nuclear aggregation and alleviation of the pathogenic phenotype by the application of potent inhibitors and RNA interference.


aggregates ataxin-1 cell therapy cellular dysfunction polyglutamine protein interaction 


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  1. Al-Ramahi, I., Lam, Y.C., Chen, H.K., de Gouyon, B., Zhang, M., Perez, A.M., Branco, J., de Haro, M., Patterson, C., Zoghbi, H.Y., et al. (2006). CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J. Biol. Chem. 281, 26714–26724.PubMedCrossRefGoogle Scholar
  2. Banfi, S., Servadio, A., Chung, M.Y., Kwiatkowski, T.J., Jr., McCall, A.E., Duvick, L.A., Shen, Y., Roth, E.J., Orr, H.T., and Zoghbi, H.Y. (1994). Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nat. Genet. 7, 513–520.PubMedCrossRefGoogle Scholar
  3. Becher, M.W., Kotzuk, J.A., Sharp, A.H., Davies, S.W., Bates, G.P., Price, D.L., and Ross, C.A. (1998). Intranuclear neuronal inclusions in Huntington’s disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol. Dis. 4, 387–397.PubMedCrossRefGoogle Scholar
  4. Burright, E.N., Davidson, J.D., Duvick, L.A., Koshy, B., Zoghbi, H.Y., and Orr, H.T. (1997). Identification of a self-association region within the SCA1 gene product, ataxin-1. Hum. Mol. Genet. 6, 513–518.PubMedCrossRefGoogle Scholar
  5. 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
  6. 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
  7. Chen, H.K., Fernandez-Funez, P., Acevedo, S.F., Lam, Y.C., Kaytor, M.D., Fernandez, M.H., Aitken, A., Skoulakis, E.M., Orr, H.T., Botas, J., et al. (2003). Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell. 113, 457–468.PubMedCrossRefGoogle Scholar
  8. Chung, M.Y., Ranum, L.P., Duvick, L.A., Servadio, A., Zoghbi, H.Y., and Orr, H.T. (1993). Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat. Genet. 5, 254–258.PubMedCrossRefGoogle Scholar
  9. 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
  10. Cummings, C.J., Orr, H.T., and Zoghbi, H.Y. (1999)a. Progress in pathogenesis studies of spinocerebellar ataxia type 1. Philos. Trans. R Soc. Lond B Biol. Sci. 354, 1079–1081.PubMedCrossRefGoogle Scholar
  11. Cummings, C.J., Reinstein, E., Sun, Y., Antalffy, B., Jiang, Y., Ciechanover, A., Orr, H.T., Beaudet, A.L., and Zoghbi, H.Y. (1999)b. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24, 879–892.PubMedCrossRefGoogle Scholar
  12. 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
  13. Cvetanovic, M., Rooney, R.J., Garcia, J.J., Toporovskaya, N., Zoghbi, H.Y., and Opal, P. (2007). The role of LANP and ataxin 1 in E4F-mediated transcriptional repression. EMBO Rep. 8, 671–677.PubMedCrossRefGoogle Scholar
  14. Davies, S.W., Turmaine, M., Cozens, B.A., DiFiglia, M., Sharp, A.H., Ross, C.A., Scherzinger, E., Wanker, E.E., Mangiarini, L., and Bates, G.P. (1997). Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548.PubMedCrossRefGoogle Scholar
  15. de Chiara, C., Giannini, C., Adinolfi, S., de Boer, J., Guida, S., Ramos, A., Jodice, C., Kioussis, D., and Pastore, A. (2003). The AXH module: an independently folded domain common to ataxin-1 and HBP1. FEBS Lett. 551, 107–112.PubMedCrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. Emamian, E.S., Kaytor, M.D., Duvick, L.A., Zu, T., Tousey, S.K., Zoghbi, H.Y., Clark, H.B., and Orr, H.T. (2003). Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38, 375–387.PubMedCrossRefGoogle Scholar
  18. Fernandez-Funez, P., Nino-Rosales, M.L., de Gouyon, B., She, W.C., Luchak, J.M., Martinez, P., Turiegano, E., Benito, J., Capovilla, M., Skinner, P.J.I et al. (2000). Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106.PubMedCrossRefGoogle Scholar
  19. Gatchel, J.R., Watase, K., Thaller, C., Carson, J.P., Jafar-Nejad, P., Shaw, C., Zu, T., Orr, H.T., and Zoghbi, H.Y. (2008). The insulinlike growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7. Proc. Natl. Acad. Sci. USA 105, 1291–1296.PubMedCrossRefGoogle Scholar
  20. Goold, R., Hubank, M., Hunt, A., Holton, J., Menon, R.P., Revesz, T., Pandolfo, M., and Matilla-Duenas, A. (2007). Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1. Hum. Mol. Genet. 16, 2122–2134.PubMedCrossRefGoogle Scholar
  21. Heiser, V., Scherzinger, E., Boeddrich, A., Nordhoff, E., Lurz, R., Schugardt, N., Lehrach, H., and Wanker, E.E. (2000). Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington’s disease therapy. Proc. Natl. Acad. Sci. USA 97, 6739–6744.PubMedCrossRefGoogle Scholar
  22. Heiser, V., Engemann, S., Brocker, W., Dunkel, I., Boeddrich, A., Waelter, S., Nordhoff, E., Lurz, R., Schugardt, N., Rautenberg, S.I. et al. (2002). Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington’s disease by using an automated filter retardation assay. Proc. Natl. Acad. Sci. USA 99, 16400–16406.PubMedCrossRefGoogle Scholar
  23. Holmberg, M., Duyckaerts, C., Durr, A., Cancel, G., Gourfinkel-An, I., Damier, P., Faucheux, B., Trottier, Y., Hirsch, E.C., Agid, Y., et al. (1998). Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum. Mol. Genet. 7, 913–918.PubMedCrossRefGoogle Scholar
  24. Hong, S., Kim, S.J., Ka, S., Choi, I., and Kang, S. (2002). USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product. Mol. Cell Neurosci. 20, 298–306.PubMedCrossRefGoogle Scholar
  25. Hong, S., Ka, S., Kim, S., Park, Y., and Kang, S. (2003). p80 coilin, a coiled body-specific protein, interacts with ataxin-1, the SCA1 gene product. Biochim. Biophys. Acta 1638, 35–42.PubMedGoogle Scholar
  26. Hong, S., Lee, S., Cho, S.G., and Kang, S. (2008). UbcH6 interacts with and ubiquitinates the SCA1 gene product ataxin-1. Biochem. Biophys. Res. Commun. 371, 256–260.PubMedCrossRefGoogle Scholar
  27. Huynh, D.P., Del Bigio, M.R., Ho, D.H., and Pulst, S.M. (1999). Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer’s disease and spinocerebellar ataxia 2. Ann. Neurol. 45, 232–241.PubMedCrossRefGoogle Scholar
  28. Irwin, S., Vandelft, M., Pinchev, D., Howell, J.L., Graczyk, J., Orr, H.T., and Truant, R. (2005). RNA association and nucleocytoplasmic shuttling by ataxin-1. J. Cell Sci. 118, 233–242.PubMedCrossRefGoogle Scholar
  29. Katsuno, M., Adachi, H., Doyu, M., Minamiyama, M., Sang, C., Kobayashi, Y., Inukai, A., and Sobue, G. (2003). Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat. Med. 9, 768–773.PubMedCrossRefGoogle Scholar
  30. Kazantsev, A., Walker, H.A., Slepko, N., Bear, J.E., Preisinger, E., Steffan, J.S., Zhu, Y.Z., Gertler, F.B., Housman, D.E., Marsh, J.L., et al. (2002). A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat. Genet. 25, 25.Google Scholar
  31. Kazemi-Esfarjani, P., and Benzer, S. (2000). Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837–1840.PubMedCrossRefGoogle Scholar
  32. Khoshnan, A., Ko, J., and Patterson, P.H. (2002). Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc. Natl. Acad. Sci. USA 99, 1002–1007.PubMedCrossRefGoogle Scholar
  33. 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 [see comments]. Cell 95, 41–53.PubMedCrossRefGoogle Scholar
  34. Lam, Y.C., Bowman, A.B., Jafar-Nejad, P., Lim, J., Richman, R., Fryer, J.D., Hyun, E.D., Duvick, L.A., Orr, H.T., Botas, J., et al. (2006). ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127, 1335–1347.PubMedCrossRefGoogle Scholar
  35. Lecerf, J.M., Shirley, T.L., Zhu, Q., Kazantsev, A., Amersdorfer, P., Housman, D.E., Messer, A., and Huston, J.S. (2001). Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington’s disease. Proc. Natl. Acad. Sci. USA 98, 4764–4769.PubMedCrossRefGoogle Scholar
  36. Lee, S., Hong, S., and Kang, S. (2008). The ubiquitin-conjugating enzyme UbcH6 regulates the transcriptional repression activity of the SCA1 gene product ataxin-1. Biochem. Biophys. Res. Commun. 372, 735–740.PubMedCrossRefGoogle Scholar
  37. Li, M., Miwa, S., Kobayashi, Y., Merry, D.E., Yamamoto, M., Tanaka, F., Doyu, M., Hashizume, Y., Fischbeck, K.H., and Sobue, G. (1998). Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann. Neurol. 44, 249–254.PubMedCrossRefGoogle Scholar
  38. Lim, J., Hao, T., Shaw, C., Patel, A.J., Szabo, G., Rual, J.F., Fisk, C.J., Li, N., Smolyar, A., Hill, D.E.I. et al. (2006). A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125, 801–814.PubMedCrossRefGoogle Scholar
  39. Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A.B., Richman, R., Hill, D.E., Orr, H.T., and Zoghbi, H.Y. (2008). Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452, 713–718.PubMedCrossRefGoogle Scholar
  40. Matilla, A., Koshy, B.T., Cummings, C.J., Isobe, T., Orr, H.T., and Zoghbi, H.Y. (1997). The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389, 974–978.PubMedCrossRefGoogle Scholar
  41. McCampbell, A., Taye, A.A., Whitty, L., Penney, E., Steffan, J.S., and Fischbeck, K.H. (2001). Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc. Natl. Acad. Sci. USA 98, 15179–15184.PubMedCrossRefGoogle Scholar
  42. Michalik, A., and Van Broeckhoven, C. (2003). Pathogenesis of polyglutamine disorders: aggregation revisited. Hum. Mol. Genet. 12, R173–186.PubMedCrossRefGoogle Scholar
  43. Mizutani, A., Wang, L., Rajan, H., Vig, P.J., Alaynick, W.A., Thaler, J.P., and Tsai, C.C. (2005). Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J. 24, 3339–3351.PubMedCrossRefGoogle Scholar
  44. Muchowski, P.J., Schaffar, G., Sittler, A., Wanker, E.E., Hayer-Hartl, M.K., and Hartl, F.U. (2000). Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. USA 97, 7841–7846.PubMedCrossRefGoogle Scholar
  45. Nagai, Y., Tucker, T., Ren, H., Kenan, D.J., Henderson, B.S., Keene, J.D., Strittmatter, W.J., and Burke, J.R. (2000). Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J. Biol. Chem. 275, 10437–10442.PubMedCrossRefGoogle Scholar
  46. Okazawa, H., Rich, T., Chang, A., Lin, X., Waragai, M., Kajikawa, M., Enokido, Y., Komuro, A., Kato, S., Shibata, M.I et al. (2002). Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron 34, 701–713.PubMedCrossRefGoogle Scholar
  47. Okuda, T., Hattori, H., Takeuchi, S., Shimizu, J., Ueda, H., Palvimo, J.J., Kanazawa, I., Kawano, H., Nakagawa, M., and Okazawa, H. (2003). PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype. Hum. Mol. Genet. 12, 711–725.PubMedCrossRefGoogle Scholar
  48. Orr, H.T. (2000). The ins and outs of a polyglutamine neurodegenerative disease: spinocerebellar ataxia type 1 (SCA1). Neurobiol. Dis. 7, 129–134.PubMedCrossRefGoogle Scholar
  49. Orr, H.T., and Zoghbi, H.Y. (2001). SCA1 molecular genetics: a history of a 13 year collaboration against glutamines. Hum. Mol. Genet. 10, 2307–2311.PubMedCrossRefGoogle Scholar
  50. Orr, H.T., and Zoghbi, H.Y. (2007). Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30, 575–621.PubMedCrossRefGoogle Scholar
  51. Orr, H.T., Chung, M.Y., Banfi, S., Kwiatkowski, T.J., Jr., Servadio, A., Beaudet, A.L., McCall, A.E., Duvick, L.A., Ranum, L.P., and Zoghbi, H.Y. (1993). Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat. Genet. 4, 221–226.PubMedCrossRefGoogle Scholar
  52. Paulson, H. (2003). Polyglutamine neurodegeneration: minding your Ps and Qs. Nat. Med. 9, 825–826.PubMedCrossRefGoogle Scholar
  53. 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
  54. Perutz, M.F., Johnson, T., Suzuki, M., and Finch, J.T. (1994). Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc. Natl. Acad. Sci. USA 91, 5355–5358.PubMedCrossRefGoogle Scholar
  55. Ren, H., Nagai, Y., Tucker, T., Strittmatter, W.J., and Burke, J.R. (2001). Amino acid sequence requirements of peptides that inhibit polyglutamine-protein aggregation and cell death. Biochem. Biophys. Res. Commun. 288, 703–710.PubMedCrossRefGoogle Scholar
  56. Riley, B.E., Zoghbi, H.Y., and Orr, H.T. (2005). SUMOylation of the polyglutamine repeat protein, ataxin-1, is dependent on a functional nuclear localization signal. J. Biol. Chem. 280, 21942–21948.PubMedCrossRefGoogle Scholar
  57. Sanchez, I., Mahlke, C., and Yuan, J. (2003). Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373–379.PubMedCrossRefGoogle Scholar
  58. Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G.P., Davies, S.W., Lehrach, H., and Wanker, E.E. (1997). Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vitro. Cell 90, 549–558.PubMedCrossRefGoogle Scholar
  59. Scherzinger, E., Sittler, A., Schweiger, K., Heiser, V., Lurz, R., Hasenbank, R., Bates, G.P., Lehrach, H., and Wanker, E.E. (1999). Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc. Natl. Acad. Sci. USA 96, 4604–4609.PubMedCrossRefGoogle Scholar
  60. Schmidt, T., Lindenberg, K.S., Krebs, A., Schols, L., Laccone, F., Herms, J., Rechsteiner, M., Riess, O., and Landwehrmeyer, G.B. (2002). Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann. Neurol. 51, 302–310.PubMedCrossRefGoogle Scholar
  61. Serra, H.G., Byam, C.E., Lande, J.D., Tousey, S.K., Zoghbi, H.Y., and Orr, H.T. (2004). Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum. Mol. Genet. 13, 2535–2543.PubMedCrossRefGoogle Scholar
  62. Serra, H.G., Duvick, L., Zu, T., Carlson, K., Stevens, S., Jorgensen, N., Lysholm, A., Burright, E., Zoghbi, H.Y., Clark, H.B., et al. (2006). RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 127, 697–708.PubMedCrossRefGoogle Scholar
  63. Servadio, A., Koshy, B., Armstrong, D., Antalffy, B., Orr, H.T., and Zoghbi, H.Y. (1995). Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nat. Genet. 10, 94–98.PubMedCrossRefGoogle Scholar
  64. Sisodia, S.S. (1998). Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell 95, 1–4.PubMedCrossRefGoogle Scholar
  65. Skinner, P.J., Koshy, B.T., Cummings, C.J., Klement, I.A., Helin, K., Servadio, A., Zoghbi, H.Y., and Orr, H.T. (1997). Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389, 971–974.PubMedCrossRefGoogle Scholar
  66. Skinner, P.J., Vierra-Green, C.A., Emamian, E., Zoghbi, H.Y., and Orr, H.T. (2002). Amino acids in a region of ataxin-1 outside of the polyglutamine tract influence the course of disease in SCA1 transgenic mice. Neuromolecular Med. 1, 33–42.PubMedCrossRefGoogle Scholar
  67. 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
  68. Su, H.L., Muguruma, K., Matsuo-Takasaki, M., Kengaku, M., Watanabe, K., and Sasai, Y. (2006). Generation of cerebellar neuron precursors from embryonic stem cells. Dev. Biol. 290, 287–296.PubMedCrossRefGoogle Scholar
  69. Tanaka, M., Machida, Y., Niu, S., Ikeda, T., Jana, N.R., Doi, H., Kurosawa, M., Nekooki, M., and Nukina, N. (2004). Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat. Med. 10, 148–154.PubMedCrossRefGoogle Scholar
  70. Taroni, F., and DiDonato, S. (2004). Pathways to motor incoordination: the inherited ataxias. Nat. Rev. Neurosci. 5, 641–655.PubMedCrossRefGoogle Scholar
  71. Thakur, A.K., and Wetzel, R. (2002). Mutational analysis of the structural organization of polyglutamine aggregates. Proc. Natl. Acad. Sci. USA 99, 17014–17019.PubMedCrossRefGoogle Scholar
  72. Tsai, C.C., Kao, H.Y., Mitzutani, A., Banayo, E., Rajan, H., McKeown, M., and Evans, R.M. (2004). Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proc. Natl. Acad. Sci. USA 101, 4047–4052.PubMedCrossRefGoogle Scholar
  73. Tsuda, H., Jafar-Nejad, H., Patel, A.J., Sun, Y., Chen, H.K., Rose, M.F., Venken, K.J., Botas, J., Orr, H.T., Bellen, H.J., et al. (2005). The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell 122, 633–644.PubMedCrossRefGoogle Scholar
  74. Ueda, H., Goto, J., Hashida, H., Lin, X., Oyanagi, K., Kawano, H., Zoghbi, H.Y., Kanazawa, I., and Okazawa, H. (2002). Enhanced SUMOylation in polyglutamine diseases. Biochem. Biophys. Res. Commun. 293, 307–313.PubMedCrossRefGoogle Scholar
  75. Watase, K., Weeber, E.J., Xu, B., Antalffy, B., Yuva-Paylor, L., Hashimoto, K., Kano, M., Atkinson, R., Sun, Y., Armstrong, D.L., et al. (2002). A long CAG repeat in the mouse sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34, 905–919.PubMedCrossRefGoogle Scholar
  76. Xia, H., Mao, Q., Eliason, S.L., Harper, S.Q., Martins, I.H., Orr, H.T., Paulson, H.L., Yang, L., Kotin, R.M., and Davidson, B.L. (2004). RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat. Med. 10, 816–820.PubMedCrossRefGoogle Scholar
  77. 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
  78. Yoshida, H., Yoshizawa, T., Shibasaki, F., Shoji, S., and Kanazawa, I. (2002). Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Neurobiol. Dis. 10, 88–99.PubMedCrossRefGoogle Scholar
  79. Yue, S., Serra, H.G., Zoghbi, H.Y., and Orr, H.T. (2001). The spinocerebellar ataxia type 1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tract. Hum. Mol. Genet. 10, 25–30.PubMedCrossRefGoogle Scholar
  80. Zoghbi, H.Y. (1995). Spinocerebellar ataxia type 1. Clin. Neurosci. 3, 5–11.PubMedGoogle Scholar
  81. Zoghbi, H.Y. (2000). Spinocerebellar ataxias. Neurobiol. Dis. 7, 523–527.PubMedCrossRefGoogle Scholar
  82. Zoghbi, H.Y., Jodice, C., Sandkuijl, L.A., Kwiatkowski, T.J., Jr., McCall, A.E., Huntoon, S.A., Lulli, P., Spadaro, M., Litt, M., Cann, H.M., and et al. (1991). The gene for autosomal dominant spinocerebellar ataxia (SCA1) maps telomeric to the HLA complex and is closely linked to the D6S89 locus in three large kindreds. Am. J. Hum. Genet. 49, 23–30.PubMedGoogle Scholar
  83. Zoghbi, H.Y., and Orr, H.T. (1995). Spinocerebellar ataxia type 1. Semin Cell Biol. 6, 29–35.PubMedCrossRefGoogle Scholar
  84. Zoghbi, H.Y., and Orr, H.T. (2000). Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247.PubMedCrossRefGoogle Scholar
  85. Zoghbi, H.Y., and Orr, H.T. (2009). Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, Spinocerebellar Ataxia Type 1. J. Biol. Chem. 284, 7425–7429.PubMedCrossRefGoogle Scholar

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© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2009

Authors and Affiliations

  1. 1.Graduate School of Life Science and BiotechnologyKorea UniversitySeoulKorea
  2. 2.Department of Clinical Laboratory Science, College of Health ScienceKorea UniversitySeoulKorea

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