Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Molecular Pathogenesis of Spinocerebellar Ataxia Type 1 Disease

  • Kang, Seongman (Graduate School of Life Science and Biotechnology, Korea University) ;
  • Hong, Sunghoi (Department of Clinical Laboratory Science, College of Health Science, Korea University)
  • Received : 2009.06.16
  • Accepted : 2009.06.19
  • Published : 2009.06.30
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Abstract

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.

Keywords

References

  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 https://doi.org/10.1074/jbc.M601603200
  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 https://doi.org/10.1038/ng0894-513
  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 https://doi.org/10.1006/nbdi.1998.0168
  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 https://doi.org/10.1093/hmg/6.4.513
  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 https://doi.org/10.1093/hmg/9.19.2811
  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 https://doi.org/10.1006/jmbi.2001.4850
  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 https://doi.org/10.1016/S0092-8674(03)00349-0
  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 https://doi.org/10.1038/ng1193-254
  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 https://doi.org/10.1038/502
  10. Cummings, C.J., Orr, H.T., and Zoghbi, H.Y. (1999a). Progress in pathogenesis studies of spinocerebellar ataxia type 1. Philos. Trans. R Soc. Lond B Biol. Sci. 354, 1079-1081 https://doi.org/10.1098/rstb.1999.0462
  11. Cummings, C.J., Reinstein, E., Sun, Y., Antalffy, B., Jiang, Y., Ciechanover, A., Orr, H.T., Beaudet, A.L., and Zoghbi, H.Y. (1999b). Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice. Neuron 24, 879-892 https://doi.org/10.1016/S0896-6273(00)81035-1
  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 https://doi.org/10.1093/hmg/10.14.1511
  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 https://doi.org/10.1038/sj.embor.7400983
  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 https://doi.org/10.1016/S0092-8674(00)80513-9
  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 https://doi.org/10.1016/S0014-5793(03)00818-4
  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 https://doi.org/10.1126/science.277.5334.1990
  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 https://doi.org/10.1016/S0896-6273(03)00258-7
  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 https://doi.org/10.1038/35040584
  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 insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7. Proc. Natl. Acad. Sci. USA 105, 1291-1296 https://doi.org/10.1073/pnas.0711257105
  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 https://doi.org/10.1093/hmg/ddm162
  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 https://doi.org/10.1073/pnas.110138997
  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 https://doi.org/10.1073/pnas.182426599
  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 https://doi.org/10.1093/hmg/7.5.913
  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 https://doi.org/10.1006/mcne.2002.1103
  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. Acta1638, 35-42 https://doi.org/10.1016/S0925-4439(03)00038-3
  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 https://doi.org/10.1016/j.bbrc.2008.04.066
  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 https://doi.org/10.1002/1531-8249(199902)45:2<232::AID-ANA14>3.0.CO;2-7
  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 https://doi.org/10.1242/jcs.01611
  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 https://doi.org/10.1038/nm878
  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
  31. Kazemi-Esfarjani, P., and Benzer, S. (2000). Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837-1840 https://doi.org/10.1126/science.287.5459.1837
  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 https://doi.org/10.1073/pnas.022631799
  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 https://doi.org/10.1016/S0092-8674(00)81781-X
  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 https://doi.org/10.1016/j.cell.2006.11.038
  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 https://doi.org/10.1073/pnas.071058398
  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 https://doi.org/10.1016/j.bbrc.2008.05.125
  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 https://doi.org/10.1002/ana.410440216
  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., et al. (2006). A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125, 801-814 https://doi.org/10.1016/j.cell.2006.03.032
  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 https://doi.org/10.1038/nature06731
  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 https://doi.org/10.1038/40159
  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 https://doi.org/10.1073/pnas.261400698
  42. Michalik, A., and Van Broeckhoven, C. (2003). Pathogenesis of polyglutamine disorders: aggregation revisited. Hum. Mol. Genet. 12, R173-186 https://doi.org/10.1093/hmg/ddg295
  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 https://doi.org/10.1038/sj.emboj.7600785
  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 https://doi.org/10.1073/pnas.140202897
  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 https://doi.org/10.1074/jbc.275.14.10437
  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 https://doi.org/10.1016/S0896-6273(02)00697-9
  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 https://doi.org/10.1093/hmg/ddg084
  48. Orr, H.T. (2000). The ins and outs of a polyglutamine neurodegenerative disease: spinocerebellar ataxia type 1(SCA1). Neurobiol. Dis.7, 129-134 https://doi.org/10.1006/nbdi.2000.0305
  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 https://doi.org/10.1093/hmg/10.20.2307
  50. Orr, H.T., and Zoghbi, H.Y. (2007). Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30, 575-621 https://doi.org/10.1146/annurev.neuro.29.051605.113042
  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 https://doi.org/10.1038/ng0793-221
  52. Paulson, H. (2003). Polyglutamine neurodegeneration: minding your Ps and Qs. Nat. Med. 9, 825-826 https://doi.org/10.1038/nm0703-825
  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 https://doi.org/10.1016/S0896-6273(00)80943-5
  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 https://doi.org/10.1073/pnas.91.12.5355
  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 https://doi.org/10.1006/bbrc.2001.5783
  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 https://doi.org/10.1074/jbc.M501677200
  57. Sanchez, I., Mahlke, C., and Yuan, J. (2003). Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373-379 https://doi.org/10.1038/nature01301
  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 vivo. Cell 90, 549-558 https://doi.org/10.1016/S0092-8674(00)80514-0
  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 https://doi.org/10.1073/pnas.96.8.4604
  60. Schmidt, T., Lindenberg, K.S., Krebs, A., Sch$\ddot{o}$ls, 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 https://doi.org/10.1002/ana.10101
  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 https://doi.org/10.1093/hmg/ddh268
  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 https://doi.org/10.1016/j.cell.2006.09.036
  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 https://doi.org/10.1038/ng0595-94
  64. Sisodia, S.S. (1998). Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell 95, 1-4 https://doi.org/10.1016/S0092-8674(00)81743-2
  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 https://doi.org/10.1038/40153
  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 https://doi.org/10.1385/NMM:1:1:33
  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 https://doi.org/10.1038/35099568
  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 https://doi.org/10.1016/j.ydbio.2005.11.010
  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 https://doi.org/10.1038/nm985
  70. Taroni, F., and DiDonato, S. (2004). Pathways to motor incoordination: the inherited ataxias. Nat. Rev. Neurosci. 5, 641-655 https://doi.org/10.1038/nrn1474
  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 https://doi.org/10.1073/pnas.252523899
  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 https://doi.org/10.1073/pnas.0400615101
  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 https://doi.org/10.1016/j.cell.2005.06.012
  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 https://doi.org/10.1016/S0006-291X(02)00211-5
  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 https://doi.org/10.1016/S0896-6273(02)00733-X
  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 https://doi.org/10.1038/nm1076
  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 https://doi.org/10.1093/hmg/11.23.2905
  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 https://doi.org/10.1006/nbdi.2002.0502
  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 https://doi.org/10.1093/hmg/10.1.25
  80. Zoghbi, H.Y. (1995). Spinocerebellar ataxia type 1. Clin. Neurosci. 3, 5-11
  81. Zoghbi, H.Y. (2000). Spinocerebellar ataxias. Neurobiol. Dis.7, 523-527 https://doi.org/10.1006/nbdi.2000.0346
  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
  83. Zoghbi, H.Y., and Orr, H.T. (1995). Spinocerebellar ataxia type 1. Semin Cell Biol. 6, 29-35 https://doi.org/10.1016/1043-4682(95)90012-8
  84. Zoghbi, H.Y., and Orr, H.T. (2000). Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217-247 https://doi.org/10.1146/annurev.neuro.23.1.217
  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 https://doi.org/10.1074/jbc.R800041200

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