Browse > Article
http://dx.doi.org/10.1007/s10059-009-0095-y

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)
Publication Information
Molecules and Cells / v.27, no.6, 2009 , pp. 621-627 More about this Journal
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
aggregates; ataxin-1; cell therapy; cellular dysfunction; polyglutamine; protein interaction;
Citations & Related Records

Times Cited By Web Of Science : 7  (Related Records In Web of Science)
연도 인용수 순위
  • Reference
1 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   DOI   PUBMED   ScienceOn
2 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   DOI   ScienceOn
3 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   DOI   ScienceOn
4 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   DOI   ScienceOn
5 Taroni, F., and DiDonato, S. (2004). Pathways to motor incoordination: the inherited ataxias. Nat. Rev. Neurosci. 5, 641-655   DOI   ScienceOn
6 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
7 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   DOI   PUBMED   ScienceOn
8 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   DOI   PUBMED   ScienceOn
9 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   DOI   PUBMED   ScienceOn
10 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   DOI   PUBMED   ScienceOn
11 Kazemi-Esfarjani, P., and Benzer, S. (2000). Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837-1840   DOI   PUBMED   ScienceOn
12 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   DOI   PUBMED   ScienceOn
13 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   DOI   PUBMED   ScienceOn
14 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   DOI   PUBMED   ScienceOn
15 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   DOI   ScienceOn
16 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   DOI   ScienceOn
17 Orr, H.T., and Zoghbi, H.Y. (2007). Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30, 575-621   DOI   ScienceOn
18 Paulson, H. (2003). Polyglutamine neurodegeneration: minding your Ps and Qs. Nat. Med. 9, 825-826   DOI   PUBMED   ScienceOn
19 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   DOI   ScienceOn
20 Sanchez, I., Mahlke, C., and Yuan, J. (2003). Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373-379   DOI   ScienceOn
21 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   DOI   ScienceOn
22 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   DOI   ScienceOn
23 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   DOI   PUBMED
24 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   DOI   PUBMED   ScienceOn
25 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   DOI   ScienceOn
26 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   DOI   ScienceOn
27 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   DOI   ScienceOn
28 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   DOI   PUBMED   ScienceOn
29 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   DOI   PUBMED   ScienceOn
30 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   DOI   PUBMED   ScienceOn
31 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   DOI   ScienceOn
32 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   DOI   ScienceOn
33 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   DOI   ScienceOn
34 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   DOI   PUBMED
35 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   DOI   ScienceOn
36 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   DOI   PUBMED   ScienceOn
37 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   DOI   ScienceOn
38 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   DOI   PUBMED
39 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   DOI   PUBMED   ScienceOn
40 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   DOI   ScienceOn
41 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   DOI   PUBMED   ScienceOn
42 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   DOI   ScienceOn
43 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   DOI   ScienceOn
44 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   DOI   ScienceOn
45 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   DOI   ScienceOn
46 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   DOI   PUBMED   ScienceOn
47 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   DOI   ScienceOn
48 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   DOI   ScienceOn
49 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   DOI   ScienceOn
50 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   DOI   PUBMED   ScienceOn
51 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   DOI   ScienceOn
52 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   DOI   ScienceOn
53 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   DOI   ScienceOn
54 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   DOI   PUBMED   ScienceOn
55 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   DOI   PUBMED   ScienceOn
56 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   DOI   ScienceOn
57 Sisodia, S.S. (1998). Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell 95, 1-4   DOI   PUBMED   ScienceOn
58 Zoghbi, H.Y. (2000). Spinocerebellar ataxias. Neurobiol. Dis.7, 523-527   DOI   PUBMED   ScienceOn
59 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   DOI   PUBMED   ScienceOn
60 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   DOI   ScienceOn
61 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   DOI   PUBMED   ScienceOn
62 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   DOI   ScienceOn
63 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   DOI   ScienceOn
64 Thakur, A.K., and Wetzel, R. (2002). Mutational analysis of the structural organization of polyglutamine aggregates. Proc. Natl. Acad. Sci. USA 99, 17014-17019   DOI   ScienceOn
65 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   DOI   ScienceOn
66 Michalik, A., and Van Broeckhoven, C. (2003). Pathogenesis of polyglutamine disorders: aggregation revisited. Hum. Mol. Genet. 12, R173-186   DOI   ScienceOn
67 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   DOI   ScienceOn
68 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   DOI   ScienceOn
69 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   DOI   ScienceOn
70 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   DOI   PUBMED   ScienceOn
71 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
72 Zoghbi, H.Y. (1995). Spinocerebellar ataxia type 1. Clin. Neurosci. 3, 5-11
73 Orr, H.T. (2000). The ins and outs of a polyglutamine neurodegenerative disease: spinocerebellar ataxia type 1(SCA1). Neurobiol. Dis.7, 129-134   DOI   PUBMED   ScienceOn
74 Zoghbi, H.Y., and Orr, H.T. (1995). Spinocerebellar ataxia type 1. Semin Cell Biol. 6, 29-35   DOI   ScienceOn
75 Zoghbi, H.Y., and Orr, H.T. (2000). Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217-247   DOI   ScienceOn
76 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   DOI   ScienceOn
77 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   DOI   ScienceOn
78 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   DOI   ScienceOn
79 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   DOI   PUBMED   ScienceOn
80 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   DOI   ScienceOn
81 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   DOI   ScienceOn
82 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   DOI   PUBMED   ScienceOn
83 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   DOI   ScienceOn
84 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   DOI   ScienceOn
85 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   DOI   ScienceOn