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Canadian Association of Neurosciences Review: Polyglutamine Expansion Neurodegenerative Diseases

Published online by Cambridge University Press:  02 December 2014

Ray Truant ,
Lynn A. Raymond ,
Jianrun Xia ,
Deborah Pinchev ,
Anjee Burtnik  and
Randy Singh Atwal
Ray Truant*
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
Lynn A. Raymond
Affiliation:
Division of Neuroscience, Department of Psychiatry and Brain Research Centre, Vancouver, BC, Canada
Jianrun Xia
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
Deborah Pinchev
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
Anjee Burtnik
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
Randy Singh Atwal
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON
*
Department of Biochemistry and Biomedical Sciences, McMaster University, HSC 4H45 1200 Main Street West, Hamilton, Ontario, L8N 3Z5, Canada.
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Abstract:

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Since the early 1990s, DNA triplet repeat expansions have been found to be the cause in an ever increasing number of genetic neurologic diseases. A subset of this large family of genetic diseases has the expansion of a CAG DNA triplet in the open reading frame of a coding exon. The result of this DNA expansion is the expression of expanded glutamine amino acid repeat tracts in the affected proteins, leading to the term, Polyglutamine Diseases, which is applied to this sub-family of diseases. To date, nine distinct genes are known to be linked to polyglutamine diseases, including Huntington's disease, Machado-Joseph Disease and spinobulbar muscular atrophy or Kennedy's disease. Most of the polyglutamine diseases are characterized clinically as spinocerebellar ataxias. Here we discuss recent successes and advancements in polyglutamine disease research, comparing these different diseases with a common genetic flaw at the level of molecular biology and early drug design for a family of diseases where many new research tools for these genetic disorders have been developed. Polyglutamine disease research has successfully used interdisciplinary collaborative efforts, informative multiple mouse genetic models and advanced tools of pharmaceutical industry research to potentially serve as the prototype model of therapeutic research and development for rare neurodegenerative diseases.

Résumé:

RÉSUMÉ:

Depuis le début des années 1990, on a découvert qu’une expansion de répétitions de triplets d’ADN était la cause d’un nombre de plus en plus considérable de maladies neurologiques d’étiologie génétique. Un sousgroupe de cette grande famille de maladies génétiques possède une expansion d’un triplet CAG dans le cadre de lecture ouvert d’un exon codant. Cette expansion de l’ADN s’exprime au niveau de la protéine atteinte par une expansion de la séquence répétée d’un acide aminé, la glutamine, ce qui a donné lieu au terme de maladies à polyglutamines, terme qui s’applique à cette sous-famille de maladies. Jusqu‘à maintenant, ce phénomène a été observé dans neuf gènes différents en relation avec des maladies à polyglutamines dont la maladie de Huntington, la maladie de Machado-Joseph et l’amyotrophie spino-bulbaire ou maladie de Kennedy. La plupart des maladies à polyglutamines se classent au point de vue clinique parmi les ataxies spino-cérébelleuses. Nous discutons des découvertes récentes et des progrès de la recherche sur les maladies à polyglutamines et nous comparons ces différentes maladies qui ont un défaut génétique commun au point de vue biologie moléculaire. Nous traitons également de « drug design » pour une famille de maladies pour lesquelles plusieurs nouveaux outils de recherche ont été développés. La recherche sur les maladies à polyglutamines a bénéficié d’une collaboration interdisciplinaire et a utilisé avec succès plusieurs modèles génétiques de souris très informatifs ainsi que des outils de pointe de la recherche pharmaceutique et servira potentiellement de prototype en recherche et développement thérapeutique pour les maladies neurodégénératives rares.

Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 33 , Issue 3 , August 2006 , pp. 278 - 291
Copyright
Copyright © The Canadian Journal of Neurological 2006

References

1. Schalling, M, Hudson, TJ, Buetow, KH, Housman, DE. Direct detection of novel expanded trinucleotide repeats in the human genome. Nat Genet. 1993; 4(2): 135–9.Google Scholar
2. Epplen, C, Epplen, JT. Expression of (cac)n/(gtg)n simple repetitive sequences in mRNA of human lymphocytes. Hum Genet. 1994; 93(1): 35–41.Google Scholar
3. La Spada, AR, Wilson, EM, Lubahn, DB, Harding, AE, Fischbeck, KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991; 352(6330): 77–9.Google Scholar
4. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell. 1993; 72(6): 971–83.Google Scholar
5. Kawaguchi, Y, Okamoto, T, Taniwaki, M, Aizawa, M, Inoue, M, Katayama, S, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994; 8(3): 221–8.Google Scholar
6. Orr, HT, Chung, MY, Banfi, S, Kwiatkowski, TJ Jr, Servadio, A, Beaudet, AL, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993; 4(3): 221–6.Google Scholar
7. Behn-Krappa, A, Doerfler, W. Enzymatic amplification of synthetic oligodeoxyribonucleotides: implications for triplet repeat expansions in the human genome. Hum Mutat. 1994; 3(1): 19–24.Google Scholar
8. Chong, SS, McCall, AE, Cota, J, Subramony, SH, Orr, HT, Hughes, MR, et al. Gametic and somatic tissue-specific heterogeneity of the expanded SCA1 CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1995; 10(3): 344–50.Google Scholar
9. Cancel, G, Abbas, N, Stevanin, G, Durr, A, Chneiweiss, H, Neri, C, et al. Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus. Am J Hum Genet. 1995; 57(4): 809–16.Google Scholar
10. Trottier, Y, Biancalana, V, Mandel, JL. Instability of CAG repeats in Huntington’s disease: relation to parental transmission and age of onset. J Med Genet. 1994; 31(5): 377–82.Google Scholar
11. Djousse, L, Knowlton, B, Hayden, MR, Almqvist, EW, Brinkman, RR, Ross, CA, et al. Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Neurogenetics. 2004; 5(2): 109–14.CrossRefGoogle Scholar
12. Li, JL, Hayden, MR, Almqvist, EW, Brinkman, RR, Durr, A, Dode, C, et al. A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. Am J Hum Genet. 2003; 73(3): 682–7.Google Scholar
13. Ashizawa, T, Dunne, PW, Ward, PA, Seltzer, WK, Richards, CS, Effects of the sex of myotonic dystrophy patients on the unstable triplet repeat in their affected offspring. Neurology. 1994; 44(1): 120–2.Google Scholar
14. Housman, D, Gain of glutamines, gain of function? Nat Genet. 1995; 10(1): 3–4.Google Scholar
15. Clarke, G, Collins, RA, Leavitt, BR, Andrews, DF, Hayden, MR, Lumsden, CJ, et al. A one-hit model of cell death in inherited neuronal degenerations. Nature. 2000; 406(6792): 195–9.Google Scholar
16. Benjamin, CM, Lashwood, A. United Kingdom experience with presymptomatic testing of individuals at 25% risk for Huntington’s disease. Clin Genet. 2000; 58(1): 41–9.CrossRefGoogle ScholarPubMed
17. Langbehn, DR, Brinkman, RR, Falush, D, Paulsen, JS, Hayden, MR. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet. 2004; 65(4): 267–77.Google Scholar
18. Mangiarini, L, Sathasivam, K, Seller, M, Cozens, B, Harper, A, Hetherington, C, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996; 87(3): 493–506.Google Scholar
19. Zu, T, Duvick, LA, Kaytor, MD, Berlinger, MS, Zoghbi, HY, Clark, HB, et al. Recovery from polyglutamine-induced neuro-degeneration in conditional SCA1 transgenic mice. J Neurosci. 2004; 24(40): 8853–61.Google Scholar
20. Emamian, ES, Kaytor, MD, Duvick, LA, Zu, T, Tousey, SK, Zoghbi, HY, et al. Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron. 2003; 38(3): 375–87.Google Scholar
21. Klement, IA, Skinner, PJ, Kaytor, MD, Yi, H, Hersch, SM, Clark, HB, et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell. 1998; 95(1): 41–53.Google Scholar
22. Burright, EN, Clark, HB, Servadio, A, Matilla, T, Feddersen, RM, Yunis, WS, et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell. 1995; 82(6): 937–48.CrossRefGoogle Scholar
23. Heiser, V, Scherzinger, E, Boeddrich, A, Nordhoff, E, Lurz, R, Schugardt, N, et al. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington’s disease therapy. Proc Natl Acad Sci USA. 2000; 97(12): 6739–44.CrossRefGoogle ScholarPubMed
24. Zhang, X, Smith, DL, Meriin, AB, Engemann, S, Russel, DE, Roark, M, et al. A potent small molecule inhibits polyglutamine aggregation in Huntington’s disease neurons and suppresses neuro-degeneration in vivo. Proc Natl Acad Sci USA. 2005; 102(3): 892–7.Google Scholar
25. Perutz, MF, Glutamine repeats and inherited neurodegenerative diseases: molecular aspects. Curr Opin Struct Biol. 1996; 6(6): 848–58.Google Scholar
26. Davies, SW, Turmaine, M, Cozens, BA, DiFiglia, M, Sharp, AH, Ross, CA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997; 90(3): 537–48.Google Scholar
27. Wheeler, VC, White, JK, Gutekunst, CA, Vrbanac, V, Weaver, M, Li, XJ, et al. 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, 2000; 9(4): 503–13.Google Scholar
28. Xia, J, Lee, DH, Taylor, J, Vandelft, M, Truant, R. Huntingtin contains a highly conserved nuclear export signal. Hum Mol Genet. 2003; 12(12): 1393–403.Google Scholar
29. Muchowski, PJ. Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones? Neuron. 2002; 35(1): 9–12.CrossRefGoogle ScholarPubMed
30. Poirier, MA, Jiang, H, Ross, CA. A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure. Hum Mol Genet. 2005; 14(6): 765–74.Google Scholar
31. Brais, B, Bouchard, JP, Xie, YG, Rochefort, DL, Chretien, N, Tome, FM, et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet. 1998; 18(2): 164–7.Google Scholar
32. Brais, B, Rouleau, GA, Bouchard, JP, Fardeau, M, Tome, FM, Oculopharyngeal muscular dystrophy. Semin Neurol. 1999; 19(1): 59–66.Google Scholar
33. Utsch, B, Becker, K, Brock, D, Lentze, MJ, Bidlingmaier, F, Ludwig, M. A novel stable polyalanine [poly(A)] expansion in the HOXA13 gene associated with hand-foot-genital syndrome: proper function of poly(A)-harbouring transcription factors depends on a critical repeat length? Hum Genet. 2002; 110(5): 488–94.Google Scholar
34. De Baere, E, Beysen, D, Oley, C, Lorenz, B, Cocquet, J, De Sutter, P, et al. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. Am J Hum Genet. 2003; 72(2): 478–87.Google Scholar
35. Kremer, HP, Kremer, GH. Demise of a neuronal population in Huntington’s disease and the importance of hyponeuronogenesis. Clin Neurol Neurosurg. 1992; 94 Suppl: S7–8.Google Scholar
36. Hayden, MR, Huntington’s chorea. 1981, Berlin; New York: Springer-Verlag. xvii. 192.Google Scholar
37. Vonsattel, JP, Myers, RH, Stevens, TJ, Ferrante, RJ, Bird, ED, Richardson, EP Jr. Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol. 1985; 44(6): 559–77.Google Scholar
38. Sapp, E, Schwarz, C, Chase, K, Bhide, PG, Young, AB, Penney, J, et al. Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol. 1997; 42(4): 604–12.Google Scholar
39. Raymond, LAG, A. Huntington’s disease: Targeting the triad. Canadian Journal of Diagnosis. 2005; April: 82-7.Google Scholar
40. Maruyama, H, Kawakami, H, Nakamura, S. Reevaluation of the exact CAG repeat length in hereditary cerebellar ataxias using highly denaturing conditions and long PCR. Hum Genet. 1996; 97(5): 591–5.Google Scholar
41. Norremolle, A, Riess, O, Epplen, JT, Fenger, K, Hasholt, L, Sorensen, SA. Trinucleotide repeat elongation in the Huntingtin gene in Huntington disease patients from 71 Danish families. Hum Mol Genet. 1993; 2(9): 1475–6.Google Scholar
42. Trottier, Y, Lutz, Y, Stevanin, G, Imbert, G, Devys, D, Cancel, G, et al. Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature. 1995; 378(6555): 403–6.Google Scholar
43. Wanker, EE, Rovira, C, Scherzinger, E, Hasenbank, R, Walter, S, Tait, D, et al. HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. Hum Mol Genet. 1997; 6(3): 48795.Google Scholar
44. Li, XJ, Li, SH, Sharp, AH, Nucifora, FC Jr., Schilling, G, Lanahan, A, et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature. 1995; 378(6555): 398–402.Google Scholar
45. Faber, PW, Barnes, GT, Srinidhi, J, Chen, J, Gusella, JF, MacDonald, ME. Huntingtin interacts with a family of WW domain proteins. Hum Mol Genet. 1998; 7(9): 1463–74.CrossRefGoogle ScholarPubMed
46. Passani, LA, Bedford, MT, Faber, PW, McGinnis, KM, Sharp, AH, Gusella, JF, et al. Huntingtin’s WW domain partners in Huntington’s disease post-mortem brain fulfill genetic criteria for direct involvement in Huntington’s disease pathogenesis. Hum Mol Genet. 2000; 9(14): 2175–82.Google Scholar
47. Block-Galarza, J, Chase, KO, Sapp, E, Vaughn, KT, Vallee, RB, DiFiglia, M, et al. Fast transport and retrograde movement of huntingtin and HAP 1 in axons. Neuroreport. 1997; 8(9-10): 2247–51.Google Scholar
48. McPherson, PS. The endocytic machinery at an interface with the actin cytoskeleton: a dynamic, hip intersection. Trends Cell Biol. 2002; 12(7): 312–5.Google Scholar
49. Ferrier, V. Hip, hip, hippi! Nat Cell Biol. 2002; 4(2): E30.Google Scholar
50. Lee, SJ, Choi, JY, Sung, YM, Park, H, Rhim, H, Kang, S. E3 ligase activity of RING finger proteins that interact with Hip-2, a human ubiquitin-conjugating enzyme. FEBS Lett. 2001; 503(1): 61–4.Google Scholar
51. Holbert, S, Denghien, I, Kiechle, T, Rosenblatt, A, Wellington, C, Hayden, MR, et al. The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc Natl Acad Sci U S A. 2001; 98(4): 1811–6.CrossRefGoogle ScholarPubMed
52. McMahon, HT, Mills, IG. COP and clathrin-coated vesicle budding: different pathways, common approaches. Curr Opin Cell Biol. 2004; 16(4): 379–91.Google Scholar
53. Wu, LG. Kinetic regulation of vesicle endocytosis at synapses. Trends Neurosci. 2004; 27(9): 548–54.Google Scholar
54. Rohrbough, J, Broadie, K. Lipid regulation of the synaptic vesicle cycle. Nat Rev Neurosci. 2005; 6(2): 139–50.Google Scholar
55. Phelps, MA, Foraker, AB, Swaan, PW. Cytoskeletal motors and cargo in membrane trafficking: opportunities for high specificity in drug intervention. Drug Discov Today. 2003; 8(11): 494–502.Google Scholar
56. Dell, KR. Dynactin polices two-way organelle traffic. J Cell Biol. 2003; 160(3): 291–3.Google Scholar
57. Pal, A, Severin, F, Lommer, B, Shevchenko, A, Zerial, M. Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington’s disease. J Cell Biol. 2006; 172(4): 605–18.Google Scholar
58. DiFiglia, M, Sapp, E, Chase, K, Schwarz, C, Meloni, A, Young, C, et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron. 1995; 14(5): 1075–81.Google Scholar
59. De Rooij, KE, Dorsman, JC, Smoor, MA, Den Dunnen, JT, Van Ommen, GJ. Subcellular localization of the Huntington’s disease gene product in cell lines by immunofluorescence and biochemical subcellular fractionation. Hum Mol Genet. 1996; 5(8): 1093–9.CrossRefGoogle ScholarPubMed
60. Zuccato, C, Tartari, M, Crotti, A, Goffredo, D, Valenza, M, Conti, L, et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet. 2003; 35(1): 76–83.Google Scholar
61. Cattaneo, E, Rigamonti, D, Zuccato, C, The enigma of Huntington’s disease. Sci Am. 2002; 287(6): 92–7.Google Scholar
62. Zuccato, C, Ciammola, A, Rigamonti, D, Leavitt, BR, Goffredo, D, Conti, L, et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science. 2001; 293(5529): 493–8.Google Scholar
63. Perez-Navarro, E, Canudas, AM, Akerund, P, Alberch, J, Arenas, E. 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. 2000; 75(5): 2190–9.CrossRefGoogle Scholar
64. Bemelmans, AP, Horellou, P, Pradier, L, Brunet, I, Colin, P, Mallet, J. 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. 1999; 10(18): 2987–97.Google Scholar
65. Nucifora, FC Jr, Ellerby, LM, Wellington, CL, Wood, JD, Herring, WJ, Sawa, A, et al. Nuclear localization of a non-caspase truncation product of atrophin-1, with an expanded polyglutamine repeat, increases cellular toxicity. J Biol Chem. 2003; 278(15): 1304755.Google Scholar
66. Steffan, JS, Kazantsev, A, Spasic-Boskovic, O, Greenwald, M, Zhu, YZ, Gohler, H, et al. The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA. 2000; 97(12): 6763–8.Google Scholar
67. Gauthier, LR, Charrin, BC, Borrell-Pages, M, Dompierre, JP, Rangone, H, Cordelieres, FP, et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004; 118(1): 127–38.Google Scholar
68. Zeitlin, S, Liu, JP, Chapman, DL, Papaioannou, VE, Efstratiadis, A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet. 1995; 11(2): 155–63.Google Scholar
69. Rosen, A. Huntingtin: new marker along the road to death? Nat Genet. 1996; 13(4): 380–2.Google Scholar
70. Wellington, CL, Ellerby, LM, Hackam, AS, Margolis, RL, Trifiro, MA, Singaraja, R, et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem. 1998; 273(15): 9158–67.Google Scholar
71. Tobin, AJ, Signer, ER. Huntington’s disease: the challenge for cell biologists. Trends Cell Biol. 2000; 10(12): 531–6.Google Scholar
72. Kells, AP, Fong, DM, Dragunow, M, During, MJ, Young, D, Connor, B. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol Ther. 2004; 9(5): 682–8.Google Scholar
73. Hillson, JL, Furst, DE. Rofecoxib. Expert Opin Pharmacother. 2000; 1(5): 1053–66.Google Scholar
74. Matsumoto, AK, Cavanaugh, PF Jr. Etoricoxib. Drugs Today (Barc). 2004; 40(5): 395–414.Google Scholar
75. Liu, S, Jiang, S. High throughput screening and characterization of HIV-1 entry inhibitors targeting gp41: theories and techniques. Curr Pharm Des. 2004; 10(15): 1827–43.Google Scholar
76. Flynn, DL, Abood, NA, Holwerda, BC. Recent advances in antiviral research: identification of inhibitors of the herpesvirus proteases. Curr Opin Chem Biol. 1997; 1(2): 190–6.Google Scholar
77. Wesche, H, Xiao, SH, Young, SW. High throughput screening for protein kinase inhibitors. Comb Chem High Throughput Screen. 2005; 8(2): 181–95.CrossRefGoogle ScholarPubMed
78. Kazantsev, A, Walker, HA, Slepko, N, Bear, JE, Preisinger, E, Steffan, JS, et al. A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat Genet. 2002; 30(4): 367–76.Google Scholar
79. Heiser, V, Engemann, S, Brocker, W, Dunkel, I, Boeddrich, A, Waelter, S, et al. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington’s disease by using an automated filter retardation assay. Proc Natl Acad Sci USA. 2002; 99 Suppl 4: S16400–6.Google Scholar
80. Pollitt, SK, Pallos, J, Shao, J, Desai, UA, Ma, AA, Thompson, LM, et al. A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor. Neuron. 2003; 40(4): 685–94.Google Scholar
81. Khoshnan, A, Ko, J, Patterson, PH. Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc Natl Acad Sci USA. 2002; 99(2): 1002–7.Google Scholar
82. Qin, ZH, Wang, Y, Sapp, E, Cuiffo, B, Wanker, E, Hayden, MR, et al. Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J Neurosci. 2004; 24(1): 26981.CrossRefGoogle ScholarPubMed
83. Wang, J, Gines, S, MacDonald, ME, Gusella, JF. Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci. 2005; 6(1): 1.Google Scholar
84. Hoshino, M, Tagawa, K, Okuda, T, Murata, M, Oyanagi, K, Arai, N, et al. Histone deacetylase activity is retained in primary neurons expressing mutant huntingtin protein. J Neurochem. 2003; 87(1): 257–67.Google Scholar
85. Steffan, JS, Bodai, L, Pallos, J, Poelman, M, McCampbell, A, Apostol, BL, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 2001; 413(6857): 739–43.Google Scholar
86. Ferrante, RJ, Kubilus, JK, Lee, J, Ryu, H, Beesen, A, Zucker, B, et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci. 2003; 23(28): 9418–27.Google Scholar
87. Bodner, RA, Outeiro, TF, Altmann, S, Maxwell, MM, Cho, SH, Hyman, BT, et al. Pharmacologinal promotion of inclusion formation: a therapeutic approach for Huntington’s and Parkinson’s diseases. Proc Natl Acad Sci USA. 2006; 103(1): 4246–51.Google Scholar
88. Stockwell, BR. Chemical genetic screening approaches to neurobiology. Neuron. 2002; 36(4): 559–62.Google Scholar
89. Jelkmann, W, Molecular biology of erythropoietin. Intern Med. 2004; 43(8): 649–59.Google Scholar
90. Barnes, PJ, Hansel, TT. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet. 2004; 364(9438): 985–96.Google Scholar
91. Alarcon de la Lastra, C, Sanchez-Fidalgo, S, Villegas, I, Motilva, V. New pharmacological perspectives and therapeutic potential of PPAR-gamma agonists. Curr Pharm Des. 2004; 10(28): 3505–24.Google Scholar
92. Lou, YR, Qiao, S, Talonpoika, R, Syvala, H, Tuohimaa, P. The role of Vitamin D3 metabolism in prostate cancer. J Steroid Biochem Mol Biol. 2004; 92(4): 317–25.Google Scholar
93. Platet, N, Cathiard, AM, Gleizes, M, Garcia, M. Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol. 2004; 51(1): 55–67.CrossRefGoogle ScholarPubMed
94. Humbert, S, Bryson, EA, Cordelieres, FP, Connors, NC, Datta, SR, Finkbeiner, S, et al. The IGF-1/Akt pathway is neuroprotective in Huntington’s disease and involves Huntingtin phosphorylation by Akt. Dev Cell. 2002; 2(6): 831–7.Google Scholar
95. Gines, S, Ivanova, E, Seong, IS, Saura, CA, MacDonald, ME. Enhanced Akt signaling is an early pro-survival response that reflects N-methyl-D-aspartate receptor activation in Huntington’s disease knock-in striatal cells. J Biol Chem. 2003; 278(50): 50514–22.Google Scholar
96. Kumar, U, Asotra, K, Patel, SC, Patel, YC. Expression of NMDA receptor-1 (NR1) and huntingtin in striatal neurons which colocalize somatostatin, neuropeptide Y, and NADPH diaphorase: a double-label histochemical and immuno-histochemical study. Exp Neurol. 1997; 145(2 Pt 1): 412–24.Google Scholar
97. Chen, N, Luo, T, Wellington, C, Metzler, M, McCutcheon, K, Hayden, MR, et al. Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin. J Neurochem. 1999; 72(5): 18908.Google Scholar
98. Zeron, MM, Chen, N, Moshaver, A, Lee, AT, Wellington, CL, Hayden, MR, et al. Mutant huntingtin enhances excitotoxic cell death. Mol Cell Neurosci. 2001; 17(1): 41–53.CrossRefGoogle ScholarPubMed
99. Anborgh, PH, Godin, C, Pampillo, M, Dhami, GK, Dale, LB, Cregan, SP, et al. Inhibition of metabotropic glutamate receptor signaling by the huntingtin-binding protein optineurin. J Biol Chem. 2005; 280(41): 34840–8.Google Scholar
100. Takano, H, Gusella, JF. The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci. 2002; 3(1): 15.Google Scholar
101. Khoshnan, A, Ko, J, Watkin, EE, Paige, LA, Reinhart, PH, Patterson, PH. Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity. J Neurosci. 2004; 24(37): 7999–8008.Google Scholar
102. Garcia, M, Charvin, D, Caboche, J. Expanded huntingtin activates the c-Jun terminal kinase/c-Jun pathway prior to aggregate formation in striatal neurons in culture. Neuroscience. 2004; 127(4): 85970.Google Scholar
103. Bezprozvanny, I, Hayden, MR. Deranged neuronal calcium signaling and Huntington disease. Biochem Biophys Res Commun. 2004; 322(4): 1310–7.CrossRefGoogle ScholarPubMed
104. Tang, TS, Slow, E, Lupu, V, Stavrovskaya, IG, Sugimori, M, Llinas, R, et al. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington’s disease. Proc Natl Acad Sci USA. 2005; 102(7): 2602–7.Google Scholar
105. Panov, AV, Lund, S, Greenamyre, JT. Ca2+-induced permeability transition in human lymphoblastoid cell mitochondria from normal and Huntington’s disease individuals. Mol Cell Biochem. 2005; 269(1-2): 143–52.Google Scholar
106. Zhuchenko, O, Bailey, J, Bonnen, P, Ashizawa, T, Stockton, DW, Amos, C, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997; 15(1): 62–9.Google Scholar
107. Matsuyama, Z, Yanagisawa, NK, Aoki, Y, Black, JL 3rd, Lennon, VA, Mori, Y, et al. Polyglutamine repeats of spinocerebellar ataxia 6 impair the cell-death-preventing effect of CaV2.1 Ca2+ channel-loss-of-function cellular model of SCA6. Neurobiol Dis. 2004; 17(2): 198–204.Google Scholar
108. Brinkmann, AO, Trapman, J. Androgen receptor mutants that affect normal growth and development. Cancer Surv. 1992; 14: 95–111.Google Scholar
109. Diamond, M, Watson, LA. Androgen insensitivity syndrome and Klinefelter’s syndrome: sex and gender considerations. Child Adolesc Psychiatr Clin N Am. 2004; 13(3): 623–40, viii.Google Scholar
110. Lingappa, VR, Blobel, G. Early events in the biosynthesis of secretory and membrane proteins: the signal hypothesis. Recent Prog Horm Res. 1980; 36: 451–75.Google Scholar
111. Saporita, AJ, Zhang, Q, Navai, N, Dincer, Z, Hahn, J, Cai, X, et al. Identification and characterization of a ligand-regulated nuclear export signal in androgen receptor. J Biol Chem. 2003; 278(43): 41998–2005.Google Scholar
112. Adachi, H, Katsuno, M, Minamiyama, M, Waza, M, Sang, C, Nakagomi, Y, et al. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain. 2005; 128(Pt 3): 659–70.CrossRefGoogle ScholarPubMed
113. Paulson, HL, Perez, MK, Trottier, Y, Trojanowski, JQ, Subramony, SH, Das, SS, et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997; 19(2): 333–44.Google Scholar
114. Suhr, ST, Senut, MC, Whitelegge, JP, Faull, KF, Cuizon, DB, Gage, FH. Identities of sequestered proteins in aggregates from cells with induced polyglutamine expression. J Cell Biol. 2001; 153(2): 283–94.Google Scholar
115. Stenoien, DL, Cummings, CJ, Adams, HP, Mancini, MG, Patel, K, DeMartino, GN, et al. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum Mol Genet. 1999; 8(5): 731–41.Google Scholar
116. Katsuno, M, Adachi, H, Kume, A, Li, M, Nakagomi, Y, Niwa, H, et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron. 2002; 35(5): 843–54.Google Scholar
117. Takeyama, K, Ito, S, Yamamoto, A, Tanimoto, H, Furutani, T, Kanuka, H, et al. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron. 2002; 35(5): 855–64.Google Scholar
118. Katsuno, M, Adachi, H, Tanaka, F, Sobue, G. Spinal and bulbar muscular atrophy: ligand-dependent pathogenesis and therapeutic perspectives. J Mol Med. 2004; 82(5): 298–307.Google Scholar
119. Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifen. Hepatology. 2004; 40(6): 1361–9.Google Scholar
120. White, JK, Auerbach, W, Duyao, MP, Vonsattel, JP, Gusella, JF, Joyner, AL, et al. Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat Genet. 1997; 17(4): 404–10.Google Scholar
121. Landwehrmeyer, GB, McNeil, SM, Dure, LS 4th, Ge, P, Aizawa, H, Huang, Q, et al. Huntington’s disease gene: regional and cellular expression in brain of normal and affected individuals. Ann Neurol. 1995; 37(2): 218–30.Google Scholar
122. Matsuyama, N, Hadano, S, Onoe, K, Osuga, H, Showguchi-Miyata, J, Gondo, Y, et al. Identification and characterization of the miniature pig Huntington’s disease gene homolog: evidence for conservation and polymorphism in the CAG triplet repeat. Genomics. 2000; 69(1): 72–85.Google Scholar
123. Orr, HT, Zoghbi, HY. SCA1 molecular genetics: a history of a 13 year collaboration against glutamines. Hum Mol Genet. 2001; 10(20): 2307–11.Google Scholar
124. Di Donato, S. The complex clinical and genetic classification of inherited ataxias. I. Dominant ataxias. Ital J Neurol Sci, 1998; 19(6): 335–43.Google Scholar
125. Taroni, F, Di Donato, S. Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci. 2004; 5(8): 641–55.Google Scholar
126. Silveira, I, Lopes-Cendes, I, Kish, S, Maciel, P, Gaspar, C, Coutinho, P, et al. Frequency of spinocerebellar ataxia type 1, dentatorubro-pallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients. Neurology. 1996; 46(1): 214–8.Google Scholar
127. van de Warrenburg, BP, Sinke, RJ, Verschuuren-Bemelmans, CC, Scheffer, H, Brunt, ER, Ippel, PF, et al. Spinocerebellar ataxias in the Netherlands: prevalence and age at onset variance analysis. Neurology. 2002; 58(5): 702–8.Google Scholar
128. Albin, RL. Dominant ataxias and Friedreich ataxia: an update. Curr Opin Neurol. 2003; 16(4): 507–14.Google Scholar
129. Schols, L, Bauer, P, Schmidt, T, Schulte, T, Riess, O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004; 3(5): 291–304.Google Scholar
130. Zoghbi, HY, Orr, HT, Glutamine repeats and neurodegeneration. Annu Rev Neurosci. 2000; 23: 217–47.Google Scholar
131. Zoghbi, HY, Orr, HT. Spinocerebellar ataxia type 1. Semin Cell Biol. 1995; 6(1): 29–35.Google Scholar
132. Ordway, JM, Tallaksen-Greene, S, Gutekunst, CA, Bernstein, EM, Cearley, JA, Wiener, HW, et al. Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell. 1997; 91(6): 753–63.Google Scholar
133. Ordway, JM, Cearley, JA, Detloff, PJ. CAG-polyglutamine-repeat mutations: independence from gene context. Philos Trans R Soc Lond B Biol Sci. 1999; 354(1386): 1083–8.Google Scholar
134. Kaytor, HK, Fernandez-Funez, P, Acevedo, SF, Lam, YC, Kaytor, MD, Fernandez, MH, et al. Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell. 2003; 113(4): 457–68.Google Scholar
135. Kaytor, MD, Byam, CE, Tousey, SK, Stevens, SD, Zoghbi, HY, Orr, HT. Acell-based screen for modulators of ataxin-1 phosphorylation. Hum Mol Genet. 2005; 14(8): 1095–105.Google Scholar
136. Yue, S, Serra, HG, Zoghbi, HY, Orr, HT. 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. 2001; 10(1): 25–30.Google Scholar
137. Tsai, CC, Kao, HY, Mitzutani, A, Banayo, E, Rajan, H, McKeown, M, et al. 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. 2004; 101(12): 4047–52.Google Scholar
138. Stenoien, DL, Mielke, M, Mancini, MA. Intranuclear ataxin1 inclusions contain both fast- and slow-exchanging components. Nat Cell Biol. 2002; 4(10): 806–10.Google Scholar
139. Irwin, S, Vandelft, M, Pinchev, D, Howell, JL, Graczyk, J, Orr, HT, et al. RNA association and nucleocytoplasmic shuttling by ataxin-1. J Cell Sci. 2005; 118(Pt 1): 233–42.Google Scholar
140. Kim, S, Nollen, EA, Kitagawa, K, Bindokas, VP, Morimoto, RI. Polyglutamine protein aggregates are dynamic. Nat Cell Biol. 2002; 4(10): 826–31.Google Scholar
141. Koyano, S, Uchihara, T, Fujigasaki, H, Nakamura, A, Yagishita, S, Iwabuchi, K. Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study. Neurosci Lett. 1999; 273(2): 117–20.Google Scholar
142. Huynh, DP, Figueroa, K, Hoang, N, Pulst, SM. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet. 2000; 26(1): 44–50.Google Scholar
143. Shibata, H, Huynh, DP, Pulst, SM. A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet. 2000; 9(9): 130313.Google Scholar
144. Albrecht, M, Golatta, M, Wullner, U, Lengauer, T. Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem. 2004; 271(15): 3155–70.Google Scholar
145. Ralser, M, Albrecht, M, Nonhoff, U, Lengauer, T, Lehrach, H, Krobitsch, S. An integrative approach to gain insights into the cellular function of human ataxin-2. J Mol Biol. 2005; 346(1): 203–14.Google Scholar
146. Pinol-Roma, S, Dreyfuss, G. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm. Nature. 1992; 355(6362): 730–2.Google Scholar
147. Jorgensen, P, Breitkreutz, BJ, Breitkreutz, K, Stark, C, Liu, G, Cook, M, et al. Harvesting the genome’s bounty: integrative genomics. Cold Spring Harb Symp Quant Biol. 2003; 68: 431–43.Google Scholar
148. Eberhart, DE, Malter, HE, Feng, Y, Warren, ST. The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Hum Mol Genet. 1996; 5(8): 1083–91.CrossRefGoogle ScholarPubMed
149. Brown, V, Jin, P, Ceman, S, Darnell, JC, O’Donnell, WT, Tenenbaum, SA, et al. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell. 2001; 107(4): 477–87.Google Scholar
150. Ule, J, Jensen, KB, Ruggiu, M, Mele, A, Ule, A, Darnell, RB. CLIP identifies Nova-regulated RNA networks in the brain. Science. 2003; 302(5648): 1212–5.Google Scholar
151. Jun, L, Frints, S, Duhamel, H, Herold, A, Abad-Rodrigues, J, Dotti, C, et al. NXF5, a novel member of the nuclear RNA export factor family, is lost in a male patient with a syndromic form of mental retardation. Curr Biol. 2001; 11(18): 1381–91.Google Scholar
152. Hayes, S, Turecki, G, Brisebois, K, Lopes-Cendes, I, Gaspar, C, Riess, O, et al. CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2). Hum Mol Genet. 2000; 9(12): 1753–8.Google Scholar
153. Gouw, LG, Digre, KB, Harris, CP, Haines, JH, Ptacek, LJ. Autosomal dominant cerebellar ataxia with retinal degeneration: clinical, neuropathologic, and genetic analysis of a large kindred. Neurology. 1994; 44(8): 1441–7.Google Scholar
154. Kaytor, MD, Duvick, LA, Skinner, PJ, Koob, MD, Ranum, LP, Orr, HT. Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7. Hum Mol Genet. 1999; 8(9): 1657–64.Google Scholar
155. Yoo, SY, Pennesi, ME, Weeber, EJ, Xu, B, Atkinson, R, Chen, S, et al. SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron. 2003; 37(3): 383–401.Google Scholar
156. Grote, SK, La Spada, AR. Insights into the molecular basis of polyglutamine neurodegeneration from studies of a spinocerebellar ataxia type 7 mouse model. Cytogenet Genome Res. 2003; 100(1-4): 164–74.Google Scholar
157. Chen, S, Peng, GH, Wang, X, Smith, AC, Grote, SK, Sopher, BL, et al. Interference of Crx-dependent transcription by ataxin-7 involves interaction between the glutamine regions and requires the ataxin-7 carboxy-terminal region for nuclear localization. Hum Mol Genet. 2004; 13(1): 53–67.Google Scholar
158. Helmlinger, D, Hardy, S, Sasorith, S, Klein, F, Robert, F, Weber, C, et al. Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet. 2004; 13(12): 1257–65.Google Scholar
159. Taylor, J, Grote, SK, Xia, J, Vandelft, M, Graczyk, J, Ellerby, LM, et al. Ataxin-7 can export from the nucleus via a conserved exportin-dependent signal. J Biol Chem. 2006; 281(5): 2730–9.Google Scholar
160. Bowman, AB, Yoo, SY, Dantuma, NP, Zoghbi, HY. 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. 2005; 14(5): 679–91.Google Scholar
161. Arrasate, M, Mitra, S, Schweitzer, ES, Segal, MR, Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature. 2004; 431(7010): 805–10.Google Scholar
162. Mushegian, AR, Vishnivetskiy, SA, Gurevich, VV. Conserved phosphoprotein interaction motif is functionally interchangeable between ataxin-7 and arrestins. Biochemistry. 2000; 39(23): 6809–13.Google Scholar
163. Lefkowitz, RJ, Shenoy, SK. Transduction of receptor signals by beta-arrestins. Science, 2005; 308(5721): 512–7.Google Scholar
164. La Spada Spada, AR, Paulson, HL, Fischbeck, KH. Trinucleotide repeat expansion in neurological disease. Ann Neurol. 1994; 36(6): 81422.Google Scholar
165. Bruni, AC, Takahashi-Fujigasaki, J, Maltecca, F, Foncin, JF, Servadio, A, Casari, G, et al. Behavioral disorder, dementia, ataxia, and rigidity in a large family with TATA box-binding protein mutation. Arch Neurol. 2004; 61(8): 1314–20.Google Scholar
166. Perez, MK, Paulson, HL, Pendse, SJ, Saionz, SJ, Bonini, NM, Pittman, RN. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol. 1998; 143(6): 1457–70.Google Scholar
167. Gunther, P, Storch, A, Schwarz, J, Sabri, O, Steinbach, P, Wagner, A, et al. Basal ganglia involvement of a patient with SCA 17--a new form of autosomal dominant spinocerebellar ataxia. J Neurol. 2004; 251(7): 896–7.Google Scholar
168. Hagenah, JM, Zuhlke, C, Hellenbroich, Y, Heide, W, Klein, C. Focal dystonia as a presenting sign of spinocerebellar ataxia 17. Mov Disord. 2004; 19(2): 217–20.Google Scholar
169. Ichikawa, Y, Goto, J, Hattori, M, Toyoda, A, Ishii, K, Jeong, SY, et al. The genomic structure and expression of MJD, the Machado-Joseph disease gene. J Hum Genet. 2001; 46(7): 413–22.Google Scholar
170. Gaspar, C, Lopes-Cendes, I, Hayes, S, Goto, J, Arvidsson, K, Dias, A, et al. Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study. Am J Hum Genet. 2001; 68(2): 523–8.Google Scholar
171. Durr, A, Stevanin, G, Cancel, G, Duyckaerts, C, Abbas, N, Didierjean, O, et al. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol. 1996; 39(4): 490–9.Google Scholar
172. Bennett, EJ, Bence, NF, Jayakumar, R, Kopito, RR. Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. Mol Cell. 2005; 17(3): 351–65.Google Scholar
173. Park, Y, Hong, S, Kim, SJ, Kang, S. Proteasome function is inhibited by polyglutamine-expanded ataxin-1, the SCA1 gene product. Mol Cells. 2005; 19(1): 23–30.Google Scholar
174. Burnett, BG, Pittman, RN. The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci USA. 2005; 102(12): 4330–5.Google Scholar
175. Goti, D, Katzen, SM, Mez, J, Kurtis, N, Kiluk, J, Ben-Haiem, L, et al. A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci. 2004; 24(45): 10266–79.CrossRefGoogle ScholarPubMed
176. Schmidt, T, Landwehrmeyer, GB, Schmitt, I, Trottier, Y, Auburger, G, Laccone, F, et al. An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol. 1998; 8(4): 669–79.Google Scholar
177. Chai, Y, Shao, J, Miller, VM, Williams, A, Paulson, HL. Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. Proc Natl Acad Sci USA. 2002; 99(14): 9310–5.Google Scholar
178. Gaspar, C, Jannatipour, M, Dion, P, Laganiere, J, Sequeiros, J, Brais, B, et al. CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Hum Mol Genet. 2000; 9(13): 195766.Google Scholar
179. Silveira, I, Manaia, A, Melki, J, Magarino, C, Lunkes, A, Hernandez, A, et al. Machado-Joseph disease is genetically different from Holguin dominant ataxia (SCA2). Genomics. 1993; 17(3): 556–9.CrossRefGoogle ScholarPubMed
180. Velazquez-Perez, L, Garcia, R, Santos, FN, Paneque, HM, Medina, HE, Hechavarria, PR. [Hereditary ataxias in Cuba. Historical, epidemiological, clinical, electrophysiological and quantitative neurological features]. Rev, Neurol, 2001; 32(1): 71–6.Google Scholar
181. Komure, O, Sano, A, Nishino, N, Yamauchi, N, Ueno, S, Kondoh, K, et al. DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation. Neurology. 1995; 45(1): 143–9.CrossRefGoogle ScholarPubMed
182. Yazawa, I, Hazeki, N, Kanazawa, I. Different complex formations of dentatorubral-pallidoluysian atrophy (DRPLA) protein in human and rat neurons. Biochem Biophys Res Commun. 1998; 253(2): 209–13.Google Scholar
183. Yazawa, I. Aberrant phosphorylation of dentatorubral-pallidoluysian atrophy (DRPLA) protein complex in brain tissue. Biochem J. 2000; 351 Pt 3: 587–93.Google Scholar
184. Schilling, G, Wood, JD, Duan, K, Slunt, HH, Gonzales, V, Yamada, M, et al. Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA. Neuron. 1999; 24(1): 27586.Google Scholar
185. Nucifora, FC Jr, Sasaki, M, Peters, MF, Huang, H, Cooper, JK, Yamada, M, et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science. 2001; 291(5512): 2423–8.CrossRefGoogle ScholarPubMed
186. Truant, R. Nucleocytplasmic Shuttling of Huntingtin and Huntington’s Disease. Clin. Neuro. Res. 2003; 3: 157–164.Google Scholar
187. Yamamoto, A, Lucas, JJ, Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell. 2000; 101(1): 57–66.Google Scholar
188. Martin-Aparicio, E, Yamamoto, A, Hernandez, F, Hen, R, Avila, J, Lucas, JJ. Proteasomal-dependent aggregate reversal and absence of cell death in a conditional mouse model of Huntington’s disease. J Neurosci. 2001; 21(22): 8772–81.CrossRefGoogle Scholar
189. Caplen, NJ. RNAi quashes polyQ. Nat Med. 2004; 10(8): 775–6.Google Scholar
190. Xia, H, Mao, Q, Eliason, SL, Harper, SQ, Martins, IH, Orr, HT, et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004; 10(8): 816–20.Google Scholar
191. Li, Y, Yokota, T, Matsumura, R, Taira, K, Mizusawa, H. Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNA. Ann Neurol. 2004; 56(1): 124–9.Google Scholar
192. Tomar, RS, Matta, H, Chaudhary, PM. Use of adeno-associated viral vector for delivery of small interfering RNA. Oncogene. 2003; 22(36): 5712–5.Google Scholar
193. Azzouz, M, Kingsman, SM, Mazarakis, ND. Lentiviral vectors for treating and modeling human CNS disorders. J Gene Med. 2004; 6(9): 951–62.Google Scholar