Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: Current insights and emerging therapeutic strategies

Molecular Neurobiology

Volumn 49, Issue 3, 2014, Pages 1513-1531

  Evers, Melvin M ^a   Toonen, Lodewijk J A ^a   Van Roon Mom, Willeke M C ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Ataxin 3; Machado Joseph disease; Polyglutamine disease; Proteolytic cleavage; RNA toxicity; Spinocerebellar ataxia type 3

Indexed keywords

ATAXIN 3; CALPAIN; CASPASE; RNA; ANTIOXIDANT; ATXN3 PROTEIN, HUMAN; NERVE PROTEIN; NUCLEAR PROTEIN; PEPTIDE; POLYGLUTAMINE; REPRESSOR PROTEIN;

HUMAN; NONHUMAN; PATHOGENESIS; PROTEIN ANALYSIS; PROTEIN FUNCTION; REVIEW; RNA ANALYSIS; SPINOCEREBELLAR DEGENERATION; ANIMAL; GENETICS; MACHADO-JOSEPH DISEASE; METABOLISM; PHYSIOLOGY; TOXICITY;

ANIMALS; ANTIOXIDANTS; HUMANS; MACHADO-JOSEPH DISEASE; NERVE TISSUE PROTEINS; NUCLEAR PROTEINS; PEPTIDES; REPRESSOR PROTEINS; RNA;

EID: 84902546919     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-013-8596-2     Document Type: Review

References (212)

1. Haberhausen G, Damian MS, Leweke F, Muller U (1995) Spinocerebellar ataxia, type 3 (SCA3) is genetically identical to Machado-Joseph disease (MJD). J Neurol Sci 132:71-75
2. Ranum LP, Lundgren JK, Schut LJ, Ahrens MJ, Perlman S, Aita J, Bird TD, Gomez C, Orr HT (1995) Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia. Am J Hum Genet 57:603-608
3. Silveira I, Lopes-Cendes I, Kish S, Maciel P, Gaspar C, Coutinho P, Botez MI, Teive H, Arruda W, Steiner CE et al (1996) Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients. Neurology 46:214-218 (Pubitemid 26156132)
4. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N (2012) The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis. Mov Disord 27:1083-1091
5. Coutinho P, Andrade C (1978) Autosomal dominant system degeneration in Portuguese families of the Azores Islands. A new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions. Neurology 28:703-709
6. Bauer PO, Nukina N (2009) The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. J Neurochem 110:1737-1765
7. Rosenberg RN (1992) Machado-Joseph disease: an autosomal dominant motor system degeneration. Mov Disord 7:193-203
8. Soong B, Cheng C, Liu R, Shan D (1997) Machado-Joseph disease: clinical, molecular, and metabolic characterization in Chinese kindreds. Ann Neurol 41:446-452 (Pubitemid 27169183)
9. Teive HA, Munhoz RP, Arruda WO, Lopes-Cendes I, Raskin S, Werneck LC, Ashizawa T (2012) Spinocerebellar ataxias: genotype-phenotype correlations in 104 Brazilian families. Clinics (Sao Paulo) 67:443-449
10. Riess O, Rub U, Pastore A, Bauer P, Schols L (2008) SCA3: neurological features, pathogenesis and animal models. Cerebellum 7:125-137
11. Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221-228 (Pubitemid 24338732)
12. Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean O, Chneiweiss H, Benomar A, Lyon-Caen O, Julien J et al (1996) Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol 39:490-499 (Pubitemid 26118004)
13. Padiath QS, Srivastava AK, Roy S, Jain S, Brahmachari SK (2005) Identification of a novel 45 repeat unstable allele associated with a disease phenotype at the MJD1/SCA3 locus. Am J Med Genet B Neuropsychiatr Genet 133B:124-126 (Pubitemid 40175630)
14. Carvalho DR, La Rocque-Ferreira A, Rizzo IM, Imamura EU, Speck-Martins CE (2008) Homozygosity enhances severity in spinocerebellar ataxia type 3. Pediatr Neurol 38:296-299 (Pubitemid 351382134)
15. Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, Dawson DM, Sudarsky L, Guimaraes J, Loureiro JE (1995) Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J Hum Genet 57:54-61
16. Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL, Fischbeck KH, Pittman RN (1997) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19:333-344 (Pubitemid 27374232)
17. Rub U, de Vos RA, Brunt ER, Sebesteny T, Schols L, Auburger G, Bohl J, Ghebremedhin E, Gierga K, Seidel K et al (2006) Spinocerebellar ataxia type 3 (SCA3): thalamic neurodegeneration occurs independently from thalamic ataxin-3 immunopositive neuronal intranuclear inclusions. Brain Pathol 16:218-227 (Pubitemid 44175236)
18. Bettencourt C, Santos C, Montiel R, Costa MC, Cruz-Morales P, Santos LR, Simoes N, Kay T, Vasconcelos J, Maciel P, Lima M (2010) Increased transcript diversity: novel splicing variants of Machado-Joseph disease gene (ATXN3). Neurogenetics 11: 193-202
19. Harris GM, Dodelzon K, Gong L, Gonzalez-Alegre P, Paulson HL (2010) Splice isoforms of the polyglutamine disease protein ataxin-3 exhibit similar enzymatic yet different aggregation properties. PLoS One 5:e13695
20. Schmidt T, Landwehrmeyer GB, Schmitt I, Trottier Y, Auburger G, Laccone F, Klockgether T, Volpel M, Epplen JT, Schols L, Riess O (1998) An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 8:669-679 (Pubitemid 28460926)
21. Trottier Y, Cancel G, An-Gourfinkel I, Lutz Y, Weber C, Brice A, Hirsch E, Mandel JL (1998) Heterogeneous intracellular localization and expression of ataxin-3. Neurobiol Dis 5:335-347 (Pubitemid 29037285)
22. Pozzi C, Valtorta M, Tedeschi G, Galbusera E, Pastori V, Bigi A, Nonnis S, Grassi E, Fusi P (2008) Study of subcellular localization and proteolysis of ataxin-3. Neurobiol Dis 30:190-200
23. Tait D, Riccio M, Sittler A, Scherzinger E, Santi S, Ognibene A, Maraldi NM, Lehrach H, Wanker EE (1998) Ataxin-3 is transported into the nucleus and associates with the nuclear matrix. Hum Mol Genet 7:991-997 (Pubitemid 28256592)
24. Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, Gotsdiner D, Fischbeck KH, Pittman RN (1997) Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol 41:453-462 (Pubitemid 27169184)
25. Todi SV, Laco MN, Winborn BJ, Travis SM, Wen HM, Paulson HL (2007) Cellular turnover of the polyglutamine disease protein ataxin-3 is regulated by its catalytic activity. J Biol Chem 282: 29348-29358 (Pubitemid 350043336)
26. Albrecht M, Golatta M, Wullner U, Lengauer T (2004) Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem 271:3155-3170 (Pubitemid 38998685)
27. Antony PM, Mantele S, Mollenkopf P, Boy J, Kehlenbach RH, Riess O, Schmidt T (2009) Identification and functional dissection of localization signals within ataxin-3. Neurobiol Dis 36:280-292
28. Macedo-Ribeiro S, Cortes L, Maciel P, Carvalho AL (2009) Nucleocytoplasmic shuttling activity of ataxin-3. PLoS One 4: e5834
29. Breuer P, Haacke A, Evert BO, Wullner U (2010) Nuclear aggregation of polyglutamine-expanded ataxin-3: fragments escape the cytoplasmic quality control. J Biol Chem 285:6532-6537
30. Mueller T, Breuer P, Schmitt I, Walter J, Evert BO, Wullner U (2009) CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3. Hum Mol Genet 18:3334-3343
31. Fei E, Jia N, Zhang T, Ma X, Wang H, Liu C, Zhang W, Ding L, Nukina N, Wang G (2007) Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3. Biochem Biophys Res Commun 357:487-492 (Pubitemid 46603157)
32. Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, Williams AJ, Cohen RE, Peng J, Paulson HL (2008) The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem 283:26436-26443
33. Burnett B, Li F, Pittman RN (2003) The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet 12:3195-3205 (Pubitemid 37508890)
34. do Carmo CM, Bajanca F, Rodrigues AJ, Tome RJ, Corthals G, Macedo-Ribeiro S, Paulson HL, Logarinho E, Maciel P (2010) Ataxin-3 plays a role in 1mouse myogenic differentiation through regulation of integrin subunit levels. PLoS One 5:e11728
35. Fang S, Weissman AM (2004) A field guide to ubiquitylation. Cell Mol Life Sci 61:1546-1561 (Pubitemid 38962038)
36. Lim KL, Lim GG (2011) K63-linked ubiquitination and neurodegeneration. Neurobiol Dis 43:9-16
37. Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, De CP (2005) Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc Natl Acad Sci USA 102:12700-12705 (Pubitemid 41279429)
38. Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A (2005) The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proc Natl Acad Sci USA 102:10493-10498 (Pubitemid 41061582)
39. Berke SJ, Chai Y, Marrs GL, Wen H, Paulson HL (2005) Defining the role of ubiquitin-interacting motifs in the polyglutamine disease protein, ataxin-3. J Biol Chem 280:32026-32034 (Pubitemid 41291954)
40. Evers MM, Tran HD, Zalachoras I, Pepers BA, Meijer OC, den Dunnen JT, van Ommen GJ, Aartsma-Rus A, van Roon-Mom WM (2013) Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: Removal of the CAG containing exon. Neurobiol Dis 58C:49-56
41. Nicastro G, Masino L, Esposito V, Menon RP, De SA, Fraternali F, Pastore A (2009) Josephin domain of ataxin-3 contains two distinct ubiquitin-binding sites. Biopolymers 91:1203-1214
42. Nicastro G, Todi SV, Karaca E, Bonvin AM, Paulson HL, Pastore A (2010) Understanding the role of the Josephin domain in the PolyUb binding and cleavage properties of ataxin-3. PLoS One 5:e12430
43. Jana NR, Dikshit P, Goswami A, Kotliarova S, Murata S, Tanaka K, Nukina N (2005) Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J Biol Chem 280:11635-11640 (Pubitemid 40418477)
44. Durcan TM, Kontogiannea M, Thorarinsdottir T, Fallon L, Williams AJ, Djarmati A, Fantaneanu T, Paulson HL, Fon EA (2011) The Machado-Joseph disease-associated mutant form of ataxin-3 regulates Parkin ubiquitination and stability. Hum Mol Genet 20:141-154
45. Durcan TM, Kontogiannea M, Bedard N, Wing SS, Fon EA (2012) Ataxin-3 deubiquitination is coupled to Parkin ubiquitination via E2 ubiquitin- conjugating enzyme. J Biol Chem 287:531-541
46. Durcan TM, Fon EA (2013) Ataxin-3 and its e3 partners: implications for Machado-Joseph disease. Front Neurol 4:46
47. Scaglione KM, Zavodszky E, Todi SV, Patury S, Xu P, Rodriguez-Lebron E, Fischer S, Konen J, Djarmati A, Peng J et al (2011) Ube2w and ataxin-3 coordinately regulate the ubiquitin ligase CHIP. Mol Cell 43:599-612
48. Todi SV, Winborn BJ, Scaglione KM, Blount JR, Travis SM, Paulson HL (2009) Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3. EMBO J 28:372-382
49. Todi SV, Scaglione KM, Blount JR, Basrur V, Conlon KP, Pastore A, Elenitoba-Johnson K, Paulson HL (2010) Activity and cellular functions of the deubiquitinating enzyme and polyglutamine disease protein ataxin-3 are regulated by ubiquitination at lysine 117. J Biol Chem 285:39303-39313
50. Zhong X, Pittman RN (2006) Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates. Hum Mol Genet 15: 2409-2420 (Pubitemid 44288695)
51. Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N (2000) Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum Mol Genet 9:1795-1803 (Pubitemid 30608613)
52. Liu Y, Ye Y (2012) Roles of p97-associated deubiquitinases in protein quality control at the endoplasmic reticulum. Curr Protein Pept Sci 13:436-446
53. Boeddrich A, Gaumer S, Haacke A, Tzvetkov N, Albrecht M, Evert BO, Muller EC, Lurz R, Breuer P, Schugardt N et al (2006) An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis. EMBO J 25:1547-1558
54. Wang Q, Li L, Ye Y (2006) Regulation of retrotranslocation by p97-associated deubiquitinating enzyme ataxin-3. J Cell Biol 174:963-971 (Pubitemid 44455185)
55. Laco MN, Cortes L, Travis SM, Paulson HL, Rego AC (2012) Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3. PLoS One 7:e43563
56. Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, Naruse S, Kimura T, Koide R, Nozaki K, Sano Y et al (2000) Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26:29-36
57. McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y, Paulson H, Sobue G, Fischbeck KH (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9:2197-2202
58. Chai Y, Shao J, Miller VM, Williams A, Paulson HL (2002) Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. Proc Natl Acad Sci USA 99:9310-9315 (Pubitemid 34764610)
59. Li F, Macfarlan T, Pittman RN, Chakravarti D (2002) Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem 277:45004-45012 (Pubitemid 36159099)
60. Burnett BG (2005) The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci USA 102:4330-4335
61. Evert BO, Araujo J, Vieira-Saecker AM, de Vos RA, Harendza S, Klockgether T, Wullner U (2006) Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J Neurosci 26:11474-11486 (Pubitemid 44772178)
62. Araujo J, Breuer P, Dieringer S, Krauss S, Dorn S, Zimmermann K, Pfeifer A, Klockgether T, Wuellner U, Evert BO (2011) FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3. Hum Mol Genet 20:2928-2941
63. Landschulz WH, Johnson PF, McKnight SL (1988) The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science 240:1759-1764
64. Orr HT (2012) Cell biology of spinocerebellar ataxia. J Cell Biol 197:167-177
65. Rodrigues AJ, do Carmo CM, Silva TL, Ferreira D, Bajanca F, Logarinho E, Logarinho P (2010) Absence of ataxin-3 leads to cytoskeletal disorganization and increased cell death. Biochim Biophys Acta 1803:1154-1163
66. Rodrigues AJ, Coppola G, Santos C, Costa MC, Ailion M, Sequeiros J, Geschwind DH, Maciel P (2007) Functional genomics and biochemical characterization of the C. elegans orthologue of the Machado-Joseph disease protein ataxin-3. FASEB J 21:1126-1136 (Pubitemid 46495702)
67. Rodrigues AJ, Neves-Carvalho A, Teixeira-Castro A, Rokka A, Corthals G, Logarinho E, Maciel P (2011) Absence of ataxin-3 leads to enhanced stress response in C. elegans. PLoS One 6:e18512
68. Alves S, Nascimento-Ferreira I, Dufour N, Hassig R, Auregan G, Nobrega C, Brouillet E, Hantraye P, Pedroso de Lima MC, Deglon N, de Almeida LP (2010) Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3? Hum Mol Genet 19:2380-2394
69. Schmitt I, Linden M, Khazneh H, Evert BO, Breuer P, Klockgether T, Wuellner U (2007) Inactivation of the mouse Atxn3 (ataxin-3) gene increases protein ubiquitination. Biochem Biophys Res Commun 362:734-739 (Pubitemid 47368155)
70. Switonski PM, Fiszer A, Kazmierska K, Kurpisz M, Krzyzosiak WJ, Figiel M (2011) Mouse ataxin-3 functional knock-out model. Neuromol Med 13:54-65
71. Boy J, Schmidt T, Wolburg H, Mack A, Nuber S, Bottcher M, Schmitt I, Holzmann C, Zimmermann F, Servadio A, Riess O (2009) Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3. Hum Mol Genet 18:4282-4295
72. Warrick JM, Morabito LM, Bilen J, Gordesky-Gold B, Faust LZ, Paulson HL, Bonini NM (2005) Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell 18:37-48 (Pubitemid 40444646)
73. Hubener J, Riess O (2010) Polyglutamine-induced neurodegeneration in SCA3 is not mitigated by non-expanded ataxin-3: conclusions from double-transgenic mouse models. Neurobiol Dis 38:116-124
74. Albrecht M, Hoffmann D, Evert BO, Schmitt I, Wullner U, Lengauer T (2003) Structural modeling of ataxin-3 reveals distant homology to adaptins. Proteins 50:355-370 (Pubitemid 36055612)
75. Jana NR, Nukina N (2004) Misfolding promotes the ubiquitination of polyglutamine-expanded ataxin-3, the defective gene product in SCA3/MJD. Neurotoxicol Res 6:523-533
76. Schmitt I, Brattig T, Gossen M, Riess O (1997) Characterization of the rat spinocerebellar ataxia type 3 gene. Neurogenetics 1:103-112 (Pubitemid 127709616)
77. Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J, Rechsteiner M, Riess O, Landwehrmeyer GB (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 (Pubitemid 34206286)
78. Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A (1996) Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 13: 196-202 (Pubitemid 26000440)
79. Evert BO, Wullner U, Schulz JB, Weller M, Groscurth P, Trottier Y, Brice A, Klockgether T (1999) High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells. Hum Mol Genet 8:1169-1176 (Pubitemid 29328984)
80. Bichelmeier U, Schmidt T, Hubener J, Boy J, Ruttiger L, Habig K, Poths S, Bonin M, Knipper M, Schmidt WJ et al (2007) Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci 27:7418-7428 (Pubitemid 47066563)
81. Nguyen HP, Hubener J, Weber JJ, Grueninger S, Riess O, Weiss A (2013) Cerebellar soluble mutant ataxin-3 level decreases during disease progression in Spinocerebellar Ataxia Type 3 mice. PLoS One 8:e62043
82. van Roon-Mom WM, Reid SJ, Faull RL, Snell RG (2005) TATA-binding protein in neurodegenerative disease. Neuroscience 133: 863-872 (Pubitemid 40814595)
83. Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN (1998) Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 143:1457-1470 (Pubitemid 29006496)
84. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, Aronin N (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990-1993 (Pubitemid 27449140)
85. Gunawardena S, Her LS, Brusch RG, Laymon RA, Niesman IR, Gordesky-Gold B, Sintasath L, Bonini NM, Goldstein LS (2003) Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40:25-40 (Pubitemid 37222462)
86. Seidel K, den Dunnen WF, Schultz C, Paulson H, Frank S, de Vos RA, Brunt ER, Deller T, Kampinga HH, Rub U (2010) Axonal inclusions in spinocerebellar ataxia type 3. Acta Neuropathol 120: 449-460
87. Nagai Y, Inui T, Popiel HA, Fujikake N, Hasegawa K, Urade Y, Goto Y, Naiki H, Toda T (2007) A toxic monomeric conformer of the polyglutamine protein. Nat Struct Mol Biol 14:332-340 (Pubitemid 46608340)
88. Petrakis S, Schaefer MH, Wanker EE, Andrade-Navarro MA (2013) Aggregation of polyQ-extended proteins is promoted by interaction with their natural coiled-coil partners. Bioessays 35:503-507
89. Streets AM, Sourigues Y, Kopito RR, Melki R, Quake SR (2013) Simultaneous measurement of amyloid fibril formation by dynamic light scattering and fluorescence reveals complex aggregation kinetics. PLoS One 8:e54541
90. Teixeira-Castro A, Ailion M, Jalles A, Brignull HR, Vilaca JL, Dias N, Rodrigues P, Oliveira JF, Neves-Carvalho A, Morimoto RI, Maciel P (2011) Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways. Hum Mol Genet 20:2996-3009
91. Haacke A, Broadley SA, Boteva R, Tzvetkov N, Hartl FU, Breuer P (2006) Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3. Hum Mol Genet 15:555-568 (Pubitemid 43205421)
92. Matsumoto M, Yada M, Hatakeyama S, Ishimoto H, Tanimura T, Tsuji S, Kakizuka A, Kitagawa M, Nakayama KI (2004) Molecular clearance of ataxin-3 is regulated by a mammalian E4. EMBO J 23: 659-669 (Pubitemid 38282397)
93. Berke SJ, Schmied FA, Brunt ER, Ellerby LM, Paulson HL (2004) Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3. J Neurochem 89:908-918 (Pubitemid 38684738)
94. Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, Doerr J, Ladewig J, Mertens J, Tuting T et al (2011) Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480:543-546
95. Takahashi T, Kikuchi S, Katada S, Nagai Y, Nishizawa M, Onodera O (2008) Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic. Hum Mol Genet 17:345-356
96. Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, Ben-Haiem L, Jenkins NA, Copeland NG, Kakizuka A, Sharp AH et al (2004) 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 24:10266-10279 (Pubitemid 39492054)
97. Hubener J, Weber JJ, Richter C, Honold L, Weiss A, Murad F, Breuer P, Wullner U, Bellstedt P, Paquet-Durand F et al (2012) Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). Hum. Mol. Genet
98. Earnshaw WC, Martins LM, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68:383-424 (Pubitemid 29449198)
99. Kim YJ, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel KB, Qin ZH, Aronin N, DiFiglia M (2001) Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci USA 98: 12784-12789 (Pubitemid 33020022)
100. Sanchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, Yuan J (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22:623-633 (Pubitemid 29159860)
101. Ellerby LM, Andrusiak RL, Wellington CL, Hackam AS, Propp SS, Wood JD, Sharp AH, Margolis RL, Ross CA, Salvesen GS et al (1999) Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity. J Biol Chem 274:8730-8736 (Pubitemid 29164670)
102. Ellerby LM, Hackam AS, Propp SS, Ellerby HM, Rabizadeh S, Cashman NR, Trifiro MA, Pinsky L, Wellington CL, Salvesen GS et al (1999) Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J Neurochem 72:185-195 (Pubitemid 29013892)
103. Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM, Frey AS, Menon AS, Li XJ, Stieg PE et al (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399:263-267 (Pubitemid 29246456)
104. Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS, Propp SS, Bromm M et al (1998) Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 273:9158-9167 (Pubitemid 28176206)
105. Strobl S, Fernandez-Catalan C, Braun M, Huber R, Masumoto H, Nakagawa K, Irie A, Sorimachi H, Bourenkow G, Bartunik H et al (2000) The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium. Proc Natl Acad Sci USA 97:588-592 (Pubitemid 30070353)
106. Haacke A, Hartl FU, Breuer P (2007) Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem 282:18851-18856 (Pubitemid 47100145)
107. Simoes AT, Goncalves N, Koeppen A, Deglon N, Kugler S, Duarte CB, de Pereira AL (2012) Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease. Brain 135:2428-2439
108. Jung J, Xu K, Lessing D, Bonini NM (2009) Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Hum Mol Genet 18:4843-4852
109. Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT (1998) Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95:41-53 (Pubitemid 28458023)
110. Colomer Gould VF, Goti D, Pearce D, Gonzalez GA, Gao H, de Bermudez LM, Jenkins NA, Copeland NG, Ross CA, Brown DR (2007) A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice. Neurobiol Dis 27:362-369 (Pubitemid 47337189)
111. Masino L, Nicastro G, Menon RP, Dal PF, Calder L, Pastore A (2004) Characterization of the structure and the amyloidogenic properties of the Josephin domain of the polyglutamine-containing protein ataxin-3. J Mol Biol 344:1021-1035 (Pubitemid 39491247)
112. Masino L, Nicastro G, De SA, Calder L, Molloy J, Pastore A (2011) The Josephin domain determines the morphological and mechanical properties of ataxin-3 fibrils. Biophys J 100:2033-2042
113. Hubener J, Vauti F, Funke C, Wolburg H, Ye Y, Schmidt T, Wolburg-Buchholz K, Schmitt I, Gardyan A, Driessen S et al (2011) N-terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation. Brain 134:1925-1942
114. Chai Y, Koppenhafer SL, Shoesmith SJ, Perez MK, Paulson HL (1999) Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet 8: 673-682 (Pubitemid 29139983)
115. Hirabayashi M, Inoue K, Tanaka K, Nakadate K, Ohsawa Y, Kamei Y, Popiel AH, Sinohara A, Iwamatsu A, Kimura Y et al (2001) VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration. Cell Death Differ 8:977-984 (Pubitemid 32994648)
116. Doss-Pepe EW, Stenroos ES, Johnson WG, Madura K (2003) Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis. Mol Cell Biol 23:6469-6483 (Pubitemid 37075759)
117. Nascimento-Ferreira I, Santos-Ferreira T, Sousa-Ferreira L, Auregan G, Onofre I, Alves S, Dufour N, Colomer Gould VF, Koeppen A, Deglon N, de Pereira AL (2011) Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease. Brain 134:1400-1415
118. Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13:805-811
119. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585-595 (Pubitemid 38715985)
120. Ajayi A, Yu X, Lindberg S, Langel U, Strom AL (2012) Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model. BMC Neurosci 13:86
121. Goswami A, Dikshit P, Mishra A, Mulherkar S, Nukina N, Jana NR (2006) Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction. Biochem Biophys Res Commun 342: 184-190 (Pubitemid 43247375)
122. Kim SJ, Kim TS, Hong S, Rhim H, Kim IY, Kang S (2003) Oxidative stimuli affect polyglutamine aggregation and cell death in human mutant ataxin-1-expressing cells. Neurosci Lett 348:21-24 (Pubitemid 37271927)
123. Miyata R, Hayashi M, Tanuma N, Shioda K, Fukatsu R, Mizutani S (2008) Oxidative stress in neurodegeneration in dentatorubralpallidoluysian atrophy. J Neurol Sci 264:133-139 (Pubitemid 350184086)
124. Yu YC, Kuo CL, Cheng WL, Liu CS, Hsieh M (2009) Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado-Joseph disease. J Neurosci Res 87:1884-1891
125. Kazachkova N, Raposo M, Montiel R, Cymbron T, Bettencourt C, Silva-Fernandes A, Silva S, Maciel P, Lima M (2013) Patterns of mitochondrial DNA damage in blood and brain tissues of a transgenic mouse model of Machado-Joseph disease. Neurodegener Dis 11:206-214
126. Laco MN, Oliveira CR, Paulson HL, Rego AC (2012) Compromised mitochondrial complex II in models of Machado-Joseph disease. Biochim Biophys Acta 1822:139-149
127. Emerit J, Edeas M, Bricaire F (2004) Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 58:39-46 (Pubitemid 38117047)
128. Riley BE, Orr HT (2006) Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes Dev 20:2183-2192
129. Evert BO, Vogt IR, Kindermann C, Ozimek L, de Vos RA, Brunt ER, Schmitt I, Klockgether T, Wullner U (2001) Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains. J Neurosci 21:5389-5396 (Pubitemid 32692137)
130. Evert BO, Vogt IR, Vieira-Saecker AM, Ozimek L, de Vos RA, Brunt ER, Klockgether T, Wullner U (2003) Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3. J Neuropathol Exp Neurol 62: 1006-1018 (Pubitemid 37229531)
131. Chou AH, Yeh TH, Ouyang P, Chen YL, Chen SY, Wang HL (2008) Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis 31:89-101
132. Li LB, Yu Z, Teng X, Bonini NM (2008) RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453: 1107-1111 (Pubitemid 351871727)
133. Wang LC, Chen KY, Pan H, Wu CC, Chen PH, Liao YT, Li C, Huang ML, Hsiao KM (2011) Muscleblind participates in RNA toxicity of expanded CAG and CUG repeats in Caenorhabditis elegans. Cell Mol Life Sci 68:1255-1267
134. McLeod CJ, O'Keefe LV, Richards RI (2005) The pathogenic agent in Drosophila models of 'polyglutamine' diseases. Hum Mol Genet 14:1041-1048 (Pubitemid 40575879)
135. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19:4439-4448
136. Fardaei M, Larkin K, Brook JD, Hamshere MG (2001) In vivo colocalisation of MBNL protein with DMPK expanded-repeat transcripts. Nucleic Acids Res 29:2766-2771 (Pubitemid 32685039)
137. Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA (2004) Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet 13: 3079-3088 (Pubitemid 40045262)
138. Mykowska A, Sobczak K, Wojciechowska M, Kozlowski P, Krzyzosiak WJ (2011) CAG repeats mimic CUG repeats in the misregulation of alternative splicing. Nucleic Acids Res 39: 8938-8951
139. Dansithong W, Paul S, Comai L, Reddy S (2005) MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1. J Biol Chem 280:5773-5780 (Pubitemid 40280057)
140. He Y, Vogelstein B, Velculescu VE, Papadopoulos N, Kinzler KW (2008) The antisense transcriptomes of human cells. Science 322: 1855-1857
141. Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, Nishida H, Yap CC, Suzuki M, Kawai J et al (2005) Antisense transcription in the mammalian transcriptome. Science 309:1564-1566
142. Cho DH, Thienes CP, Mahoney SE, Analau E, Filippova GN, Tapscott SJ (2005) Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol Cell 20:483-489 (Pubitemid 41572304)
143. Chung DW, Rudnicki DD, Yu L, Margolis RL (2011) A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression. Hum Mol Genet 20:3467-3477
144. Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS, Chen G, Weatherspoon MR, Clark HB, Ebner TJ et al (2006) Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet 38:758-769 (Pubitemid 43980596)
145. Wilburn B, Rudnicki DD, Zhao J, Weitz TM, Cheng Y, Gu X, Greiner E, Park CS, Wang N, Sopher BL et al (2011) An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice. Neuron 70:427-440
146. Sopher BL, Ladd PD, Pineda VV, Libby RT, Sunkin SM, Hurley JB, Thienes CP, Gaasterland T, Filippova GN, La Spada AR (2011) CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA. Neuron 70: 1071-1084
147. Banez-Coronel M, Porta S, Kagerbauer B, Mateu-Huertas E, Pantano L, Ferrer I, Guzman M, Estivill X, Marti E (2012) A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity. PLoS Genet 8: e1002481
148. Rau F, Freyermuth F, Fugier C, Villemin JP, Fischer MC, Jost B, Dembele D, Gourdon G, Nicole A, Duboc D et al (2011) Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol 18:840-845
149. Sinha M, Mukhopadhyay S, Bhattacharyya NP (2012) Mechanism(s) of alteration of micro RNA expressions in Huntington's disease and their possible contributions to the observed cellular and molecular dysfunctions in the disease. Neuromol Med 14:221-243
150. Bilen J, Liu N, Burnett BG, Pittman RN, Bonini NM (2006) MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Mol Cell 24:157-163 (Pubitemid 44466675)
151. Davies JE, Rubinsztein DC (2006) Polyalanine and polyserine frame-shift products in Huntington's disease. J Med Genet 43:893-896 (Pubitemid 44787117)
152. Gaspar C, Jannatipour M, Dion P, Laganiere J, Sequeiros J, Brais B, Rouleau GA (2000) CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Hum Mol Genet 9:1957-1966
153. Stochmanski SJ, Therrien M, Laganiere J, Rochefort D, Laurent S, Karemera L, Gaudet R, Vyboh K, Van Meyel DJ, Di CG et al (2012) Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models. Hum Mol Genet 21:2211-2218
154. Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA et al (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci USA 108:260-265
155. Pearson CE (2011) Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLoS Genet 7:e1002018
156. Paulson H (2012) Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol 103:437-449
157. Buhmann C, Bussopulos A, Oechsner M (2003) Dopaminergic response in Parkinsonian phenotype of Machado-Joseph disease. Mov Disord 18:219-221 (Pubitemid 36305470)
158. Takei A, Fukazawa T, Hamada T, Sohma H, Yabe I, Sasaki H, Tashiro K (2004) Effects of tandospirone on "5-HT1A receptor-associated symptoms" in patients with Machado-Josephe disease: an open-label study. Clin Neuropharmacol 27:9-13 (Pubitemid 38280381)
159. Bettencourt C, Lima M (2011) Machado-Joseph disease: from first descriptions to new perspectives. Orphanet J Rare Dis 6:35
160. Ogawa M (2004) Pharmacological treatments of cerebellar ataxia. Cerebellum 3:107-111
161. Nobrega C, Nascimento-Ferreira I, Onofre I, Albuquerque D, Hirai H, Deglon N, de Almeida LP (2013) Silencing mutant ataxin-3 rescues motor deficits and neuropathology in Machado-Joseph disease transgenic mice. PLoS One 8:e52396
162. Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC (2010) Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133:93-104
163. Jia DD, Zhang L, Chen Z, Wang CR, Huang FZ, Duan RH, Xia K, Tang BS, Jiang H (2013) Lithium Chloride Alleviates Neurodegeneration Partly by Inhibiting Activity of GSK3beta in a SCA3 Drosophila Model. Cerebellum.
164. Saute JA, Castilhos R, Monte T, Schuh A, Donis K, D'Ávila R et al (2013) Safety and effectiveness of lithium carbonate for the treatment of Machado-Joseph disease: A phase 2/3 randomised, double-blind, placebo-controlled trial [abstract]. Movement Disord 28(Suppl 1):713
165. Wang HL, Hu SH, Chou AH, Wang SS, Weng YH, Yeh TH (2013) H1152 promotes the degradation of polyglutamine-expanded ataxin-3 or ataxin-7 independently of its ROCK-inhibiting effect and ameliorates mutant ataxin-3-induced neurodegeneration in the SCA3 transgenic mouse. Neuropharmacology 70:1-11
166. Johri A, Beal MF (2012) Antioxidants in Huntington's disease. Biochim Biophys Acta 1822:664-674
167. Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L et al (2006) Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Neurology 66:250-252 (Pubitemid 43970166)
168. Hyson HC, Kieburtz K, Shoulson I, McDermott M, Ravina B, de Blieck EA, Cudkowicz ME, Ferrante RJ, Como P, Frank S et al (2010) Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects. Mov Disord 25: 1924-1928
169. Chen X, Tang TS, Tu H, Nelson O, Pook M, Hammer R, Nukina N, Bezprozvanny I (2008) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci 28:12713-12724
170. Makarewicz D, Zieminska E, Lazarewicz JW (2003) Dantrolene inhibits NMDA-induced 45Ca uptake in cultured cerebellar granule neurons. Neurochem Int 43:273-278 (Pubitemid 36561278)
171. Lin CM, Neeru S, Doufas AG, Liem E, Muneer SY, Wadhwa A, Lenhardt R, Bjorksten A, Taguchi A, Kabon B et al (2004) Dantrolene reduces the threshold and gain for shivering. Anesth Analg 98:1318-1324, table (Pubitemid 38525586)
172. Muehlschlegel S, Rordorf G, Sims J (2011) Effects of a single dose of dantrolene in patients with cerebral vasospasm after subarachnoid hemorrhage: a prospective pilot study. Stroke 42: 1301-1306
173. Cunha RA, Agostinho PM (2010) Chronic caffeine consumption preventsmemory disturbance in different animalmodels of memory decline. J Alzheimers Dis 20(Suppl 1):S95-S116
174. Goncalves N, Simoes AT, Cunha RA, de Almeida LP (2013) Caffeine and adenosine A(2A) receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado-Joseph disease. Ann Neurol 73:655-666
175. Popoli P, Blum D, Martire A, Ledent C, Ceruti S, Abbracchio MP (2007) Functions, dysfunctions and possible therapeutic relevance of adenosine A2A receptors in Huntington's disease. Prog Neurobiol 81:331-348 (Pubitemid 46528642)
176. Chou AH, Chen SY, Yeh TH, Weng YH, Wang HL (2011) HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3. Neurobiol Dis 41:481-488
177. Minamiyama M, Katsuno M, Adachi H, Waza M, Sang C, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Sobue G (2004) Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 13:1183-1192 (Pubitemid 38787000)
178. Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ (1995) Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood 85:43-49
179. Hogarth P, Lovrecic L, Krainc D (2007) Sodium phenylbutyrate in Huntington's disease: a dose-finding study. Mov Disord 22: 1962-1964 (Pubitemid 350134213)
180. Valentino KL, Gutierrez M, Sanchez R, Winship MJ, Shapiro DA (2003) First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes. Int J Clin Pharmacol Ther 41:441-449 (Pubitemid 37258860)
181. Baskin-Bey ES, Washburn K, Feng S, Oltersdorf T, Shapiro D, Huyghe M, Burgart L, Garrity-Park M, van Vilsteren FG, Oliver LK et al (2007) Clinical trial of the pan-caspase inhibitor, IDN-6556, in Human Liver Preservation Injury. Am J Transplant 7: 218-225 (Pubitemid 44952876)
182. Li Z, Sheng M (2012) Caspases in synaptic plasticity. Mol Brain 5:15
183. Troy CM, Salvesen GS (2002) Caspases on the brain. J Neurosci Res 69:145-150 (Pubitemid 34734145)
184. Carragher NO (2006) Calpain inhibition: a therapeutic strategy targeting multiple disease states. Curr Pharm Des 12:615-638
185. Donkor IO (2011) Calpain inhibitors: a survey of compounds reported in the patent and scientific literature. Progr Neurobiol 81:331-348
186. Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, Sobue G (2003) Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. J Neurosci 23:2203-2211 (Pubitemid 36368908)
187. Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT, Dillmann WH, Zoghbi HY (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 10:1511-1518 (Pubitemid 32684893)
188. Chan HY, Warrick JM, Gray-Board PHL, Bonini NM (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9:2811-2820
189. Muchowski PJ, Schaffar G, Sittler A, Wanker EE, Hayer-Hartl MK, Hartl FU (2000) Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Natl Acad Sci USA 97:7841-7846 (Pubitemid 30460735)
190. Bailey CK, Andriola IF, Kampinga HH, Merry DE (2002) Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum Mol Genet 11:515-523 (Pubitemid 34257488)
191. Verhoef LG, Lindsten K, Masucci MG, Dantuma NP (2002) Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum Mol Genet 11:2689-2700
192. Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, 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 (Pubitemid 34775462)
193. Wood NI, Pallier PN, Wanderer J, Morton AJ (2007) Systemic administration of Congo red does not improve motor or cognitive function in R6/2 mice. Neurobiol Dis 25:342-353 (Pubitemid 46124014)
194. Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PA, Bates GP, Hockly E (2003) Minocycline and doxycycline are not beneficial in a model of Huntington's disease. Ann Neurol 54:186-196 (Pubitemid 36909617)
195. Schilling G, Savonenko AV, Coonfield ML, Morton JL, Vorovich E, Gale A, Neslon C, Chan N, Eaton M, Fromholt D et al (2004) Environmental, pharmacological, and geneticmodulation of the HD phenotype in transgenic mice. Exp Neurol 187:137-149 (Pubitemid 38470019)
196. Wang CE, Zhou H, McGuire JR, Cerullo V, Lee B, Li SH, Li XJ (2008) Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol 181:803-816 (Pubitemid 351786985)
197. Snyder-Keller A, McLear JA, Hathorn T, Messer A (2010) Early or late-stage anti-N-terminal Huntingtin intrabody gene therapy reduces pathological features in B6.HDR6/1 mice. J Neuropathol Exp Neurol 69:1078-1085
198. Kvam E, Nannenga BL, Wang MS, Jia Z, Sierks MR, Messer A (2009) Conformational targeting of fibrillar polyglutamine proteins in live cells escalates aggregation and cytotoxicity. PLoS One 4:e5727
199. Rodriguez-Lebron E, Paulson HL (2006) Allele-specific RNA interference for neurological disease. Gene Ther 13:576-581
200. Miller VM, Xia H, Marrs GL, Gouvion CM, Lee G, Davidson BL, Paulson HL (2003) Allele-specific silencing of dominant disease genes. Proc Natl Acad Sci USA 100:7195-7200 (Pubitemid 36706415)
201. Alves S, Nascimento-Ferreira I, Auregan G, Hassig R, Dufour N, Brouillet E, Pedroso de Lima MC, Hantraye P, de Pereira AL, Deglon N (2008) Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease. PLoS One 3:e3341
202. Gaspar C, Lopes-Cendes I, Hayes S, Goto J, Arvidsson K, Dias A, Silveira I, Maciel P, Coutinho P, Lima M et al (2001) Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study. Am J Hum Genet 68:523-528 (Pubitemid 32147823)
203. Tabernero J, Shapiro GI, Lorusso PM, Cervantes A, Schwartz GK, Weiss GJ, Paz-Ares L, Cho DC, Infante JR, Alsina M et al (2013) First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov 3:406-417
204. Evers MM, Pepers BA, van Deutekom JC, Mulders SA, den Dunnen JT, Aartsma-Rus A, van Ommen GJ, van Roon-Mom WM (2011) Targeting several CAG expansion diseases by a single antisense oligonucleotide. PLoS One 6:e24308
205. Hu J, Gagnon KT, Liu J, Watts JK, Syeda-Nawaz J, Bennett CF, Swayze EE, Randolph J, Chattopadhyaya J, Corey DR (2011) Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs. Biol Chem 392:315-325
206. Liu J, Pendergraff H, Narayanannair KJ, Lackey JG, Kuchimanchi S, Rajeev KG, Manoharan M, Hu J, Corey DR (2013) RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression. Nucleic Acids Res.
207. Liu J, Yu D, Aiba Y, Pendergraff H, Swayze EE, Lima WF, Hu J, Prakash TP, Corey DR (2013) ss-siRNAs allele selectively inhibit ataxin-3 expression: multiple mechanisms for an alternative gene silencing strategy. Nucleic Acids Res..
208. Spitali P, Aartsma-Rus A (2012) Splice modulating therapies for human disease. Cell 148:1085-1088
209. Zalachoras I, Evers MM, van Roon-Mom WM, Aartsma-Rus AM, Meijer OC (2011) Antisense-mediated RNA targeting: versatile and expedient genetic manipulation in the brain. Front Mol Neurosci 4:10
210. Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, Artates JW, Weiss A, Cheng SH, Shihabuddin LS et al (2012) Sustained therapeutic reversal of huntington's disease by transient repression of huntingtin synthesis. Neuron 74:1031-1044
211. Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K et al (2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 12:435-442
212. Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, Bourke J, Wells DJ et al (2011) Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 378:595-605