Advertisement

From Pathogenesis to Novel Therapeutics for Spinocerebellar Ataxia Type 3: Evading Potholes on the Way to Translation

  • Jorge Diogo Da Silva
  • Andreia Teixeira-Castro
  • Patrícia MacielEmail author
Review

Abstract

Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease (MJD), is a neurodegenerative disorder caused by a polyglutamine expansion in the ATXN3 gene. In spite of the identification of a clear monogenic cause 25 years ago, the pathological process still puzzles researchers, impairing prospects for an effective therapy. Here, we propose the disruption of protein homeostasis as the hub of SCA3 pathogenesis, being the molecular mechanisms and cellular pathways that are deregulated in SCA3 downstream consequences of the misfolding and aggregation of ATXN3. Moreover, we attempt to provide a realistic perspective on how the translational/clinical research in SCA3 should evolve. This was based on molecular findings, clinical and epidemiological characteristics, studies of proposed treatments in other conditions, and how that information is essential for their (re-)application in SCA3. This review thus aims i) to critically evaluate the current state of research on SCA3, from fundamental to translational and clinical perspectives; ii) to bring up the current key questions that remain unanswered in this disorder; and iii) to provide a frame on how those answers should be pursued.

Keywords

Spinocerebellar ataxia type 3 Machado-Joseph disease Ataxin-3 Neurodegeneration Molecular pathogenesis Therapeutic advances 

Notes

Acknowledgments

The authors thank all the members of the Maciel lab for their helpful tips and discussion. This work was funded by the European Regional Development Fund (FEDER), through the Competitiveness Internationalization Operational Programme (POCI), and by national funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-0 31987. Moreover, the work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the FEDER (project NORTE-01-0145-FEDER-000013). A fellowship supporting the development of this work was attributed by FCT to J. D. Da S. (PD/BD/128074/2016).

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2019_798_MOESM1_ESM.pdf (462 kb)
ESM 1 (PDF 461 kb)

References

  1. 1.
    Lima L, Coutinho P. Clinical criteria for diagnosis of Machado-Joseph disease: report of a non-Azorena Portuguese family. Neurology. United States; 1980;30:319–22.CrossRefGoogle Scholar
  2. 2.
    Takiyama Y, Nishizawa M, Tanaka H, Kawashima S, Sakamoto H, Karube Y, et al. The gene for Machado-Joseph disease maps to human chromosome 14q. Nat Genet. United States; 1993;4:300–4.CrossRefGoogle Scholar
  3. 3.
    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. United States; 1994;8:221–8.Google Scholar
  4. 4.
    Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, et al. Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J Hum Genet. United States; 1995;57:54–61.Google Scholar
  5. 5.
    Wang G, Ide K, Nukina N, Goto J, Ichikawa Y, Uchida K, et al. Machado-Joseph disease gene product identified in lymphocytes and brain. Biochem Biophys Res Commun. United States; 1997;233:476–9.CrossRefGoogle Scholar
  6. 6.
    Bettencourt C, Lima M. Machado-Joseph Disease: from first descriptions to new perspectives. Orphanet J Rare Dis. England; 2011;6:35.CrossRefGoogle Scholar
  7. 7.
    Moro A, Munhoz RP, Arruda WO, Raskin S, Moscovich M, Teive HAG. Spinocerebellar ataxia type 3: subphenotypes in a cohort of Brazilian patients. Arq Neuropsiquiatr. Brazil; 2014;72:659–62.CrossRefGoogle Scholar
  8. 8.
    Sudarsky L, Coutinho P. Machado-Joseph disease. Clin Neurosci. United States; 1995;3:17–22.Google Scholar
  9. 9.
    Gwinn-Hardy K, Singleton A, O’Suilleabhain P, Boss M, Nicholl D, Adam A, et al. Spinocerebellar ataxia type 3 phenotypically resembling Parkinson disease in a black family. Arch Neurol. United States; 2001;58:296–9.CrossRefGoogle Scholar
  10. 10.
    Taroni F, DiDonato S. Pathways to motor incoordination: the inherited ataxias. Nat Rev Neurosci. England; 2004;5:641–55.CrossRefGoogle Scholar
  11. 11.
    Rub U, Brunt ER, Deller T. New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease). Curr Opin Neurol. England; 2008;21:111–6.CrossRefGoogle Scholar
  12. 12.
    D’Abreu A, Franca MCJ, Paulson HL, Lopes-Cendes I. Caring for Machado-Joseph disease: current understanding and how to help patients. Parkinsonism Relat Disord. England; 2010;16:2–7.CrossRefGoogle Scholar
  13. 13.
    Klinke I, Minnerop M, Schmitz-Hubsch T, Hendriks M, Klockgether T, Wullner U, et al. Neuropsychological features of patients with spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. Cerebellum. United States; 2010;9:433–42.CrossRefGoogle Scholar
  14. 14.
    Scherzed W, Brunt ER, Heinsen H, de Vos RA, Seidel K, Burk K, et al. Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Cerebellum. United States; 2012;11:749–60.CrossRefGoogle Scholar
  15. 15.
    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. United States; 1996;39:490–9.CrossRefGoogle Scholar
  16. 16.
    Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, Gotsdiner D, et al. Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol. United States; 1997;41:453–62.CrossRefGoogle Scholar
  17. 17.
    Yamada M, Hayashi S, Tsuji S, Takahashi H. Involvement of the cerebral cortex and autonomic ganglia in Machado-Joseph disease. Acta Neuropathol. Germany; 2001;101:140–4.Google Scholar
  18. 18.
    Munoz E, Rey MJ, Mila M, Cardozo A, Ribalta T, Tolosa E, et al. Intranuclear inclusions, neuronal loss and CAG mosaicism in two patients with Machado-Joseph disease. J Neurol Sci. Netherlands; 2002;200:19–25.CrossRefGoogle Scholar
  19. 19.
    Yamada M, Sato T, Tsuji S, Takahashi H. CAG repeat disorder models and human neuropathology: similarities and differences. Acta Neuropathol. Germany; 2008;115:71–86.CrossRefGoogle Scholar
  20. 20.
    Alves S, Regulier E, Nascimento-Ferreira I, Hassig R, Dufour N, Koeppen A, et al. Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease. Hum Mol Genet. England; 2008;17:2071–83.CrossRefGoogle Scholar
  21. 21.
    Murata Y, Yamaguchi S, Kawakami H, Imon Y, Maruyama H, Sakai T, et al. Characteristic magnetic resonance imaging findings in Machado-Joseph disease. Arch Neurol. United States; 1998;55:33–7.CrossRefGoogle Scholar
  22. 22.
    Tokumaru AM, Kamakura K, Maki T, Murayama S, Sakata I, Kaji T, et al. Magnetic resonance imaging findings of Machado-Joseph disease: histopathologic correlation. J Comput Assist Tomogr. United States; 2003;27:241–8.CrossRefGoogle Scholar
  23. 23.
    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. United States; 1997;19:333–44.CrossRefGoogle Scholar
  24. 24.
    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. Switzerland; 1998;8:669–79.CrossRefGoogle Scholar
  25. 25.
    Rub U, Brunt ER, Petrasch-Parwez E, Schols L, Theegarten D, Auburger G, et al. Degeneration of ingestion-related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7. Neuropathol Appl Neurobiol. England; 2006;32:635–49.CrossRefGoogle Scholar
  26. 26.
    Rub U, de Vos RAI, Brunt ER, Sebesteny T, Schols L, Auburger G, et al. Spinocerebellar ataxia type 3 (SCA3): thalamic neurodegeneration occurs independently from thalamic ataxin-3 immunopositive neuronal intranuclear inclusions. Brain Pathol. Switzerland; 2006;16:218–27.CrossRefGoogle Scholar
  27. 27.
    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. England; 2004;431:805–10.CrossRefGoogle Scholar
  28. 28.
    Takahashi T, Katada S, Onodera O. Polyglutamine diseases: where does toxicity come from? what is toxicity? where are we going? J Mol Cell Biol. United States; 2010;2:180–91.CrossRefGoogle Scholar
  29. 29.
    Hayashi M, Kobayashi K, Furuta H. Immunohistochemical study of neuronal intranuclear and cytoplasmic inclusions in Machado-Joseph disease. Psychiatry Clin Neurosci. Australia; 2003;57:205–13.CrossRefGoogle Scholar
  30. 30.
    Seidel K, den Dunnen WFA, Schultz C, Paulson H, Frank S, de Vos RA, et al. Axonal inclusions in spinocerebellar ataxia type 3. Acta Neuropathol. Germany; 2010;120:449–60.CrossRefGoogle Scholar
  31. 31.
    Seidel K, Siswanto S, Brunt ERP, den Dunnen W, Korf H-W, Rüb U. Brain pathology of spinocerebellar ataxias. Acta Neuropathol. Springer; 2012;124:1–21.CrossRefGoogle Scholar
  32. 32.
    Balch WE, Morimoto RI, Dillin A, Kelly JW. Adapting proteostasis for disease intervention. Science. United States; 2008;319:916–9.Google Scholar
  33. 33.
    Klaips CL, Jayaraj GG, Hartl FU. Pathways of cellular proteostasis in aging and disease. J Cell Biol. United States; 2018;217:51–63.CrossRefGoogle Scholar
  34. 34.
    Hipp MS, Park S-H, Hartl FU. Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol. England; 2014;24:506–14.CrossRefGoogle Scholar
  35. 35.
    Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol. England; 2019;20:421–35.CrossRefGoogle Scholar
  36. 36.
    Jahn TR, Radford SE. The Yin and Yang of protein folding. FEBS J. England; 2005;272:5962–70.CrossRefGoogle Scholar
  37. 37.
    Carvalho AL, Silva A, Macedo-Ribeiro S. Polyglutamine-Independent Features in Ataxin-3 Aggregation and Pathogenesis of Machado-Joseph Disease. Adv Exp Med Biol. United States; 2018;1049:275–88.CrossRefGoogle Scholar
  38. 38.
    Ellisdon AM, Thomas B, Bottomley SP. The two-stage pathway of ataxin-3 fibrillogenesis involves a polyglutamine-independent step. J Biol Chem. United States; 2006;281:16888–96.CrossRefGoogle Scholar
  39. 39.
    Gales L, Cortes L, Almeida C, Melo C V, Costa M do C, Maciel P, et al. Towards a structural understanding of the fibrillization pathway in Machado-Joseph’s disease: trapping early oligomers of non-expanded ataxin-3. J Mol Biol. England; 2005;353:642–54.CrossRefGoogle Scholar
  40. 40.
    Bevivino AE, Loll PJ. An expanded glutamine repeat destabilizes native ataxin-3 structure and mediates formation of parallel beta -fibrils. Proc Natl Acad Sci U S A. United States; 2001;98:11955–60.CrossRefGoogle Scholar
  41. 41.
    Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. United States; 2003;300:486–9.Google Scholar
  42. 42.
    Berke SJS, Schmied FAF, Brunt ER, Ellerby LM, Paulson HL. Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3. J Neurochem. England; 2004;89:908–18.CrossRefGoogle Scholar
  43. 43.
    Haacke A, Broadley SA, Boteva R, Tzvetkov N, Hartl FU, Breuer P. Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3. Hum Mol Genet. England; 2006;15:555–68.CrossRefGoogle Scholar
  44. 44.
    Breuer P, Haacke A, Evert BO, Wullner U. Nuclear aggregation of polyglutamine-expanded ataxin-3: fragments escape the cytoplasmic quality control. J Biol Chem. United States; 2010;285:6532–7.CrossRefGoogle Scholar
  45. 45.
    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. United States; 1998;273:9158–67.CrossRefGoogle Scholar
  46. 46.
    Jung J, Xu K, Lessing D, Bonini NM. Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Hum Mol Genet. England; 2009;18:4843–52.CrossRefGoogle Scholar
  47. 47.
    Liman J, Deeg S, Voigt A, Vossfeldt H, Dohm CP, Karch A, et al. CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration. J Neurochem. England; 2014;129:1013–23.CrossRefGoogle Scholar
  48. 48.
    Haacke A, Hartl FU, Breuer P. Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem. United States; 2007;282:18851–6.CrossRefGoogle Scholar
  49. 49.
    Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, et al. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature. England; 2011;480:543–6.CrossRefGoogle Scholar
  50. 50.
    Hubener J, Weber JJ, Richter C, Honold L, Weiss A, Murad F, et al. Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). Hum Mol Genet. England; 2013;22:508–18.CrossRefGoogle Scholar
  51. 51.
    Nobrega C, Simoes AT, Duarte-Neves J, Duarte S, Vasconcelos-Ferreira A, Cunha-Santos J, et al. Molecular Mechanisms and Cellular Pathways Implicated in Machado-Joseph Disease Pathogenesis. Adv Exp Med Biol. United States; 2018;1049:349–67.CrossRefGoogle Scholar
  52. 52.
    Simoes AT, Goncalves N, Koeppen A, Deglon N, Kugler S, Duarte CB, et al. Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease. Brain. England; 2012;135:2428–39.CrossRefGoogle Scholar
  53. 53.
    Chai Y, Koppenhafer SL, Shoesmith SJ, Perez MK, Paulson HL. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet. England; 1999;8:673–82.CrossRefGoogle Scholar
  54. 54.
    Chai Y, Koppenhafer SL, Bonini NM, Paulson HL. Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J Neurosci. United States; 1999;19:10338–47.CrossRefGoogle Scholar
  55. 55.
    Chai Y, Wu L, Griffin JD, Paulson HL. The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease. J Biol Chem. United States; 2001;276:44889–97.CrossRefGoogle Scholar
  56. 56.
    Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J, et al. 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. United States; 2002;51:302–10.CrossRefGoogle Scholar
  57. 57.
    Donaldson KM, Li W, Ching KA, Batalov S, Tsai C-C, Joazeiro CAP. Ubiquitin-mediated sequestration of normal cellular proteins into polyglutamine aggregates. Proc Natl Acad Sci U S A. United States; 2003;100:8892–7.CrossRefGoogle Scholar
  58. 58.
    Yang H, Li J-J, Liu S, Zhao J, Jiang Y-J, Song A-X, et al. Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: implication in a loss-of-function pathology. Sci Rep. England; 2014;4:6410.CrossRefGoogle Scholar
  59. 59.
    Kim S, Nollen EAA, Kitagawa K, Bindokas VP, Morimoto RI. Polyglutamine protein aggregates are dynamic. Nat Cell Biol. England; 2002;4:826–31.CrossRefGoogle Scholar
  60. 60.
    Olzscha H, Schermann SM, Woerner AC, Pinkert S, Hecht MH, Tartaglia GG, et al. Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell. United States; 2011;144:67–78.Google Scholar
  61. 61.
    Freeman BC, Yamamoto KR. Disassembly of transcriptional regulatory complexes by molecular chaperones. Science. United States; 2002;296:2232–5.Google Scholar
  62. 62.
    Sousa R, Lafer EM. The role of molecular chaperones in clathrin mediated vesicular trafficking. Front Mol Biosci. Switzerland; 2015;2:26.Google Scholar
  63. 63.
    Streicher JM. The Role of Heat Shock Proteins in Regulating Receptor Signal Transduction. Mol Pharmacol. United States; 2019;95:468–74.Google Scholar
  64. 64.
    Yu A, Shibata Y, Shah B, Calamini B, Lo DC, Morimoto RI. Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition. Proc Natl Acad Sci U S A. United States; 2014;111:E1481–90.CrossRefGoogle Scholar
  65. 65.
    Park S-H, Kukushkin Y, Gupta R, Chen T, Konagai A, Hipp MS, et al. PolyQ proteins interfere with nuclear degradation of cytosolic proteins by sequestering the Sis1p chaperone. Cell. United States; 2013;154:134–45.Google Scholar
  66. 66.
    Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science. United States; 2006;311:1471–4.Google Scholar
  67. 67.
    Doss-Pepe EW, Stenroos ES, Johnson WG, Madura K. 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. United States; 2003;23:6469–83.CrossRefGoogle Scholar
  68. 68.
    Burnett B, Li F, Pittman RN. The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet. England; 2003;12:3195–205.CrossRefGoogle Scholar
  69. 69.
    Wang H, Ying Z, Wang G. Ataxin-3 regulates aggresome formation of copper-zinc superoxide dismutase (SOD1) by editing K63-linked polyubiquitin chains. J Biol Chem. United States; 2012;287:28576–85.CrossRefGoogle Scholar
  70. 70.
    do Carmo Costa M, Bajanca F, Rodrigues A-J, Tome RJ, Corthals G, Macedo-Ribeiro S, et al. Ataxin-3 plays a role in mouse myogenic differentiation through regulation of integrin subunit levels. PLoS One. United States; 2010;5:e11728.CrossRefGoogle Scholar
  71. 71.
    Neves-Carvalho A, Logarinho E, Freitas A, Duarte-Silva S, Costa M do C, Silva-Fernandes A, et al. Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells. Hum Mol Genet. England; 2015;24:100–17.CrossRefGoogle Scholar
  72. 72.
    Liu H, Li X, Ning G, Zhu S, Ma X, Liu X, et al. The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53. PLoS Biol. United States; 2016;14:e2000733.CrossRefGoogle Scholar
  73. 73.
    Chai Y, Berke SS, Cohen RE, Paulson HL. Poly-ubiquitin Binding by the Polyglutamine Disease Protein Ataxin-3 Links Its Normal Function to Protein Surveillance Pathways. J Biol Chem [Internet]. 2004;279:3605–11. Available from: http://www.jbc.org/content/279/5/3605.abstract PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Winborn BJ, Travis SM, Todi S V, Scaglione KM, Xu P, Williams AJ, et al. The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem. United States; 2008;283:26436–43.Google Scholar
  75. 75.
    Teixeira-Castro A, Ailion M, Jalles A, Brignull HR, Vilaca JL, Dias N, et al. Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways. Hum Mol Genet. England; 2011;20:2996–3009.Google Scholar
  76. 76.
    Zhong X, Pittman RN. Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates. Hum Mol Genet. England; 2006;15:2409–20.CrossRefGoogle Scholar
  77. 77.
    Durcan TM, Kontogiannea M, Thorarinsdottir T, Fallon L, Williams AJ, Djarmati A, et al. The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and stability. Hum Mol Genet. England; 2011;20:141–54.CrossRefGoogle Scholar
  78. 78.
    Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science. United States; 2001;292:1552–5.Google Scholar
  79. 79.
    Matsumoto M, Yada M, Hatakeyama S, Ishimoto H, Tanimura T, Tsuji S, et al. Molecular clearance of ataxin-3 is regulated by a mammalian E4. EMBO J. England; 2004;23:659–69.CrossRefGoogle Scholar
  80. 80.
    Tsai YC, Fishman PS, Thakor N V, Oyler GA. Parkin facilitates the elimination of expanded polyglutamine proteins and leads to preservation of proteasome function. J Biol Chem. United States; 2003;278:22044–55.Google Scholar
  81. 81.
    Jana NR, Dikshit P, Goswami A, Kotliarova S, Murata S, Tanaka K, et al. Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J Biol Chem. United States; 2005;280:11635–40.CrossRefGoogle Scholar
  82. 82.
    Blount JR, Tsou W-L, Ristic G, Burr AA, Ouyang M, Galante H, et al. Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun. England; 2014;5:4638.CrossRefGoogle Scholar
  83. 83.
    Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN, et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet. England; 2006;15:433–42.CrossRefGoogle Scholar
  84. 84.
    Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain. England; 2010;133:93–104.CrossRefGoogle Scholar
  85. 85.
    Ashkenazi A, Bento CF, Ricketts T, Vicinanza M, Siddiqi F, Pavel M, et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature. England; 2017;545:108–11.CrossRefGoogle Scholar
  86. 86.
    Nascimento-Ferreira I, Santos-Ferreira T, Sousa-Ferreira L, Auregan G, Onofre I, Alves S, et al. Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado–Joseph disease. Brain [Internet]. 2011;134:1400–15. Available from:  https://doi.org/10.1093/brain/awr047 PubMedCrossRefGoogle Scholar
  87. 87.
    Sittler A, Muriel M-P, Marinello M, Brice A, den Dunnen W, Alves S. Deregulation of autophagy in postmortem brains of Machado-Joseph disease patients. Neuropathology. Australia; 2018;38:113–24.CrossRefGoogle Scholar
  88. 88.
    Duarte-Silva S, Neves-Carvalho A, Soares-Cunha C, Teixeira-Castro A, Oliveira P, Silva-Fernandes A, et al. Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease. Cerebellum. United States; 2014;13:713–27.CrossRefGoogle Scholar
  89. 89.
    Nascimento-Ferreira I, Nobrega C, Vasconcelos-Ferreira A, Onofre I, Albuquerque D, Aveleira C, et al. Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado-Joseph disease. Brain. England; 2013;136:2173–88.CrossRefGoogle Scholar
  90. 90.
    Silva-Fernandes A, Duarte-Silva S, Neves-Carvalho A, Amorim M, Soares-Cunha C, Oliveira P, et al. Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease. Neurotherapeutics. United States; 2014;11:433–49.CrossRefGoogle Scholar
  91. 91.
    Cunha-Santos J, Duarte-Neves J, Carmona V, Guarente L, Pereira de Almeida L, Cavadas C. Caloric restriction blocks neuropathology and motor deficits in Machado-Joseph disease mouse models through SIRT1 pathway. Nat Commun. England; 2016;7:11445.CrossRefGoogle Scholar
  92. 92.
    Marcelo A, Brito F, Carmo-Silva S, Matos CA, Alves-Cruzeiro J, Vasconcelos-Ferreira A, et al. Cordycepin activates autophagy through AMPK phosphorylation to reduce abnormalities in Machado-Joseph disease models. Hum Mol Genet. England; 2019;28:51–63.CrossRefGoogle Scholar
  93. 93.
    Nobrega C, Mendonca L, Marcelo A, Lamaziere A, Tome S, Despres G, et al. Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia. Acta Neuropathol. Germany; 2019Google Scholar
  94. 94.
    Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, et al. Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar Purkinje cells. Cerebellum. United States; 2014;13:29–41.CrossRefGoogle Scholar
  95. 95.
    Duarte-Silva S, Silva-Fernandes A, Neves-Carvalho A, Soares-Cunha C, Teixeira-Castro A, Maciel P. Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease. Neuroscience. United States; 2016;313:162–73.Google Scholar
  96. 96.
    Burnett BG, Pittman RN. The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci U S A. United States; 2005;102:4330–5.CrossRefGoogle Scholar
  97. 97.
    Olzmann JA, Li L, Chin LS. Aggresome formation and neurodegenerative diseases: therapeutic implications. Curr Med Chem. United Arab Emirates; 2008;15:47–60.Google Scholar
  98. 98.
    Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N. Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum Mol Genet. England; 2000;9:1795–803.CrossRefGoogle Scholar
  99. 99.
    Yang H, Yue H-W, He W-T, Hong J-Y, Jiang L-L, Hu H-Y. PolyQ-expanded huntingtin and ataxin-3 sequester ubiquitin adaptors hHR23B and UBQLN2 into aggregates via conjugated ubiquitin. FASEB J Off Publ Fed Am Soc Exp Biol. United States; 2018;32:2923–33.Google Scholar
  100. 100.
    Tsou W-L, Ouyang M, Hosking RR, Sutton JR, Blount JR, Burr AA, et al. The deubiquitinase ataxin-3 requires Rad23 and DnaJ-1 for its neuroprotective role in Drosophila melanogaster. Neurobiol Dis. United States; 2015;82:12–21.CrossRefGoogle Scholar
  101. 101.
    Sutton JR, Blount JR, Libohova K, Tsou W-L, Joshi GS, Paulson HL, et al. Interaction of the polyglutamine protein ataxin-3 with Rad23 regulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3. Hum Mol Genet. England; 2017;26:1419–31.CrossRefGoogle Scholar
  102. 102.
    Chatterjee A, Saha S, Chakraborty A, Silva-Fernandes A, Mandal SM, Neves-Carvalho A, et al. The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3’-phosphatase in spinocerebellar ataxia type 3 pathogenesis. PLoS Genet. United States; 2015;11:e1004749.CrossRefGoogle Scholar
  103. 103.
    Gao R, Liu Y, Silva-Fernandes A, Fang X, Paulucci-Holthauzen A, Chatterjee A, et al. Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3. PLoS Genet. United States; 2015;11:e1004834.CrossRefGoogle Scholar
  104. 104.
    Ward JM, La Spada AR. Ataxin-3, DNA damage repair, and SCA3 cerebellar degeneration: on the path to parsimony? PLoS Genet. United States; 2015;11:e1004937.CrossRefGoogle Scholar
  105. 105.
    Chou A-H, Lin A-C, Hong K-Y, Hu S-H, Chen Y-L, Chen J-Y, et al. p53 activation mediates polyglutamine-expanded ataxin-3 upregulation of Bax expression in cerebellar and pontine nuclei neurons. Neurochem Int. England; 2011;58:145–52.CrossRefGoogle Scholar
  106. 106.
    Bras J, Alonso I, Barbot C, Costa MM, Darwent L, Orme T, et al. Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4. Am J Hum Genet. United States; 2015;96:474–9.CrossRefGoogle Scholar
  107. 107.
    Tzoulis C, Sztromwasser P, Johansson S, Gjerde IO, Knappskog P, Bindoff LA. PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema. Cerebellum. United States; 2017;16:272–5.CrossRefGoogle Scholar
  108. 108.
    Shibata Y, Morimoto RI. How the nucleus copes with proteotoxic stress. Curr Biol. England; 2014;24:R463–74.CrossRefGoogle Scholar
  109. 109.
    Jones RD, Gardner RG. Protein quality control in the nucleus. Curr Opin Cell Biol. England; 2016;40:81–9.CrossRefGoogle Scholar
  110. 110.
    Samant RS, Livingston CM, Sontag EM, Frydman J. Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control. Nature. England; 2018;563:407–11.CrossRefGoogle Scholar
  111. 111.
    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. United States; 1998;143:1457–70.CrossRefGoogle Scholar
  112. 112.
    Bichelmeier U, Schmidt T, Hubener J, Boy J, Ruttiger L, Habig K, et al. Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci. United States; 2007;27:7418–28.CrossRefGoogle Scholar
  113. 113.
    McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet. England; 2000;9:2197–202.CrossRefGoogle Scholar
  114. 114.
    Li F, Macfarlan T, Pittman RN, Chakravarti D. Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem. United States; 2002;277:45004–12.CrossRefGoogle Scholar
  115. 115.
    Evert BO, Araujo J, Vieira-Saecker AM, de Vos RAI, Harendza S, Klockgether T, et al. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J Neurosci. United States; 2006;26:11474–86.CrossRefGoogle Scholar
  116. 116.
    Araujo J, Breuer P, Dieringer S, Krauss S, Dorn S, Zimmermann K, et al. FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3. Hum Mol Genet. England; 2011;20:2928–41.CrossRefGoogle Scholar
  117. 117.
    Chou A-H, Yeh T-H, Ouyang P, Chen Y-L, Chen S-Y, Wang H-L. Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis. United States; 2008;31:89–101.CrossRefGoogle Scholar
  118. 118.
    Chou A-H, Chen S-Y, Yeh T-H, Weng Y-H, Wang H-L. HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3. Neurobiol Dis. United States; 2011;41:481–8.CrossRefGoogle Scholar
  119. 119.
    Chou A-H, Chen Y-L, Hu S-H, Chang Y-M, Wang H-L. Polyglutamine-expanded ataxin-3 impairs long-term depression in Purkinje neurons of SCA3 transgenic mouse by inhibiting HAT and impairing histone acetylation. Brain Res. Netherlands; 2014;1583:220–9.CrossRefGoogle Scholar
  120. 120.
    Esteves S, Duarte-Silva S, Naia L, Neves-Carvalho A, Teixeira-Castro A, Rego AC, et al. Limited Effect of Chronic Valproic Acid Treatment in a Mouse Model of Machado-Joseph Disease. PLoS One. United States; 2015;10:e0141610.CrossRefGoogle Scholar
  121. 121.
    Wiatr K, Piasecki P, Marczak L, Wojciechowski P, Kurkowiak M, Ploski R, et al. Altered Levels of Proteins and Phosphoproteins, in the Absence of Early Causative Transcriptional Changes, Shape the Molecular Pathogenesis in the Brain of Young Presymptomatic Ki91 SCA3/MJD Mouse. Mol Neurobiol. United States; 2019Google Scholar
  122. 122.
    Toonen LJA, Overzier M, Evers MM, Leon LG, van der Zeeuw SAJ, Mei H, et al. Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model. Mol Neurodegener. England; 2018;13:31.CrossRefGoogle Scholar
  123. 123.
    Li Y, Yokota T, Gama V, Yoshida T, Gomez JA, Ishikawa K, et al. Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation. Cell Death Differ. England; 2007;14:2058–67.CrossRefGoogle Scholar
  124. 124.
    Yi J, Zhang L, Tang B, Han W, Zhou Y, Chen Z, et al. Sodium valproate alleviates neurodegeneration in SCA3/MJD via suppressing apoptosis and rescuing the hypoacetylation levels of histone H3 and H4. PLoS One. United States; 2013;8:e54792.CrossRefGoogle Scholar
  125. 125.
    Lin XP, Feng L, Xie CG, Chen DB, Pei Z, Liang XL, et al. Valproic acid attenuates the suppression of acetyl histone H3 and CREB activity in an inducible cell model of Machado-Joseph disease. Int J Dev Neurosci. England; 2014;38:17–22.CrossRefGoogle Scholar
  126. 126.
    Wang Z-J, Hanet A, Weishaupl D, Martins IM, Sowa AS, Riess O, et al. Divalproex sodium modulates nuclear localization of ataxin-3 and prevents cellular toxicity caused by expanded ataxin-3. CNS Neurosci Ther. England; 2018;24:404–11.CrossRefGoogle Scholar
  127. 127.
    Carmona V, Cunha-Santos J, Onofre I, Simoes AT, Vijayakumar U, Davidson BL, et al. Unravelling Endogenous MicroRNA System Dysfunction as a New Pathophysiological Mechanism in Machado-Joseph Disease. Mol Ther. United States; 2017;25:1038–55.CrossRefGoogle Scholar
  128. 128.
    Evert BO, Nalavade R, Jungverdorben J, Matthes F, Weber S, Rajput A, et al. Upregulation of miR-370 and miR-543 is associated with reduced expression of heat shock protein 40 in spinocerebellar ataxia type 3. PLoS One. United States; 2018;13:e0201794.CrossRefGoogle Scholar
  129. 129.
    Krauss S, Nalavade R, Weber S, Carter K, Evert BO. Upregulation of miR-25 and miR-181 Family Members Correlates with Reduced Expression of ATXN3 in Lymphocytes from SCA3 Patients. MicroRNA (Shariqah, United Arab Emirates). United Arab Emirates; 2019;8:76–85.Google Scholar
  130. 130.
    Fei E, Jia N, Zhang T, Ma X, Wang H, Liu C, et al. Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3. Biochem Biophys Res Commun. United States; 2007;357:487–92.CrossRefGoogle Scholar
  131. 131.
    Mueller T, Breuer P, Schmitt I, Walter J, Evert BO, Wullner U. CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3. Hum Mol Genet. England; 2009;18:3334–43.CrossRefGoogle Scholar
  132. 132.
    Matos CA, Nobrega C, Louros SR, Almeida B, Ferreiro E, Valero J, et al. Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models. J Cell Biol. United States; 2016;212:465–80.CrossRefGoogle Scholar
  133. 133.
    Todi S V, Winborn BJ, Scaglione KM, Blount JR, Travis SM, Paulson HL. Ubiquitination directly enhances activity of the deubiquitinating enzyme ataxin-3. EMBO J. England; 2009;28:372–82.CrossRefGoogle Scholar
  134. 134.
    Todi S V, Scaglione KM, Blount JR, Basrur V, Conlon KP, Pastore A, et al. Activity and cellular functions of the deubiquitinating enzyme and polyglutamine disease protein ataxin-3 are regulated by ubiquitination at lysine 117. J Biol Chem. United States; 2010;285:39303–13.CrossRefGoogle Scholar
  135. 135.
    Tsou W-L, Burr AA, Ouyang M, Blount JR, Scaglione KM, Todi S V. Ubiquitination regulates the neuroprotective function of the deubiquitinase ataxin-3 in vivo. J Biol Chem. United States; 2013;288:34460–9.Google Scholar
  136. 136.
    Zhou Y-F, Liao S-S, Luo Y-Y, Tang J-G, Wang J-L, Lei L-F, et al. SUMO-1 modification on K166 of polyQ-expanded ataxin-3 strengthens its stability and increases its cytotoxicity. PLoS One. United States; 2013;8:e54214.CrossRefGoogle Scholar
  137. 137.
    Almeida B, Abreu IA, Matos CA, Fraga JS, Fernandes S, Macedo MG, et al. SUMOylation of the brain-predominant Ataxin-3 isoform modulates its interaction with p97. Biochim Biophys Acta. Netherlands; 2015;1852:1950–9.Google Scholar
  138. 138.
    Pozzi C, Valtorta M, Tedeschi G, Galbusera E, Pastori V, Bigi A, et al. Study of subcellular localization and proteolysis of ataxin-3. Neurobiol Dis. United States; 2008;30:190–200.CrossRefGoogle Scholar
  139. 139.
    Kristensen L V, Oppermann FS, Rauen MJ, Fog K, Schmidt T, Schmidt J, et al. Mass spectrometry analyses of normal and polyglutamine expanded ataxin-3 reveal novel interaction partners involved in mitochondrial function. Neurochem Int. England; 2018;112:5–17.CrossRefGoogle Scholar
  140. 140.
    Matsuishi T, Sakai T, Naito E, Nagamitsu S, Kuroda Y, Iwashita H, et al. Elevated cerebrospinal fluid lactate/pyruvate ratio in Machado-Joseph disease. Acta Neurol Scand. Denmark; 1996;93:72–5.CrossRefGoogle Scholar
  141. 141.
    Tsai H-F, Tsai H-J, Hsieh M. Full-length expanded ataxin-3 enhances mitochondrial-mediated cell death and decreases Bcl-2 expression in human neuroblastoma cells. Biochem Biophys Res Commun. United States; 2004;324:1274–82.CrossRefGoogle Scholar
  142. 142.
    Chou A-H, Yeh T-H, Kuo Y-L, Kao Y-C, Jou M-J, Hsu C-Y, et al. Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL. Neurobiol Dis. United States; 2006;21:333–45.CrossRefGoogle Scholar
  143. 143.
    Yu Y-C, Kuo C-L, Cheng W-L, Liu C-S, Hsieh M. Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado-Joseph disease. J Neurosci Res. United States; 2009;87:1884–91.CrossRefGoogle Scholar
  144. 144.
    Laco MN, Oliveira CR, Paulson HL, Rego AC. Compromised mitochondrial complex II in models of Machado-Joseph disease. Biochim Biophys Acta. Netherlands; 2012;1822:139–49.Google Scholar
  145. 145.
    Kazachkova N, Raposo M, Montiel R, Cymbron T, Bettencourt C, Silva-Fernandes A, et al. Patterns of mitochondrial DNA damage in blood and brain tissues of a transgenic mouse model of Machado-Joseph disease. Neurodegener Dis. Switzerland; 2013;11:206–14.CrossRefGoogle Scholar
  146. 146.
    Ramos A, Kazachkova N, Silva F, Maciel P, Silva-Fernandes A, Duarte-Silva S, et al. Differential mtDNA damage patterns in a transgenic mouse model of Machado-Joseph disease (MJD/SCA3). J Mol Neurosci. United States; 2015;55:449–53.CrossRefGoogle Scholar
  147. 147.
    Harmuth T, Prell-Schicker C, Weber JJ, Gellerich F, Funke C, Driessen S, et al. Mitochondrial Morphology, Function and Homeostasis Are Impaired by Expression of an N-terminal Calpain Cleavage Fragment of Ataxin-3. Front Mol Neurosci. Switzerland; 2018;11:368.CrossRefGoogle Scholar
  148. 148.
    Duarte-Silva S, Neves-Carvalho A, Soares-Cunha C, Silva JM, Teixeira-Castro A, Vieira R, et al. Neuroprotective Effects of Creatine in the CMVMJD135 Mouse Model of Spinocerebellar Ataxia Type 3. Mov Disord. United States; 2018;33:815–26.CrossRefGoogle Scholar
  149. 149.
    Hubener J, Vauti F, Funke C, Wolburg H, Ye Y, Schmidt T, et al. N-terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation. Brain. England; 2011;134:1925–42.CrossRefGoogle Scholar
  150. 150.
    Hampton RY. ER-associated degradation in protein quality control and cellular regulation. Curr Opin Cell Biol. England; 2002;14:476–82.CrossRefGoogle Scholar
  151. 151.
    Kostova Z, Wolf DH. For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. EMBO J. England; 2003;22:2309–17.CrossRefGoogle Scholar
  152. 152.
    McCracken AA, Brodsky JL. Evolving questions and paradigm shifts in endoplasmic-reticulum-associated degradation (ERAD). Bioessays. United States; 2003;25:868–77.CrossRefGoogle Scholar
  153. 153.
    Ye Y, Meyer HH, Rapoport TA. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature. England; 2001;414:652–6.CrossRefGoogle Scholar
  154. 154.
    Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf DH, et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol. England; 2002;4:134–9.CrossRefGoogle Scholar
  155. 155.
    Romisch K. Endoplasmic reticulum-associated degradation. Annu Rev Cell Dev Biol. United States; 2005;21:435–56.Google Scholar
  156. 156.
    Boeddrich A, Gaumer S, Haacke A, Tzvetkov N, Albrecht M, Evert BO, et al. An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis. EMBO J. England; 2006;25:1547–58.CrossRefGoogle Scholar
  157. 157.
    Fardghassemi Y, Tauffenberger A, Gosselin S, Parker JA. Rescue of ATXN3 neuronal toxicity in Caenorhabditiselegans by chemical modification of endoplasmic reticulum stress. Dis Model Mech. England; 2017;10:1465–80.CrossRefGoogle Scholar
  158. 158.
    Chen X, Tang T-S, Tu H, Nelson O, Pook M, Hammer R, et al. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci. United States; 2008;28:12713–24.CrossRefGoogle Scholar
  159. 159.
    Pellistri F, Bucciantini M, Invernizzi G, Gatta E, Penco A, Frana AM, et al. Different ataxin-3 amyloid aggregates induce intracellular Ca(2+) deregulation by different mechanisms in cerebellar granule cells. Biochim Biophys Acta. Netherlands; 2013;1833:3155–65.Google Scholar
  160. 160.
    Zhivotovsky B, Orrenius S. Calcium and cell death mechanisms: a perspective from the cell death community. Cell Calcium. Netherlands; 2011;50:211–21.CrossRefGoogle Scholar
  161. 161.
    Klockgether T, Schols L, Abele M, Burk K, Topka H, Andres F, et al. Age related axonal neuropathy in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). J Neurol Neurosurg Psychiatry. England; 1999;66:222–4.CrossRefGoogle Scholar
  162. 162.
    D’Abreu A, Franca MJ, Appenzeller S, Lopes-Cendes I, Cendes F. Axonal dysfunction in the deep white matter in Machado-Joseph disease. J Neuroimaging. United States; 2009;19:9–12.CrossRefGoogle Scholar
  163. 163.
    Khan LA, Bauer PO, Miyazaki H, Lindenberg KS, Landwehrmeyer BG, Nukina N. Expanded polyglutamines impair synaptic transmission and ubiquitin-proteasome system in Caenorhabditis elegans. J Neurochem. England; 2006;98:576–87.CrossRefGoogle Scholar
  164. 164.
    Teixeira-Castro A, Jalles A, Esteves S, Kang S, da Silva Santos L, Silva-Fernandes A, et al. Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Brain. England; 2015;138:3221–37.CrossRefGoogle Scholar
  165. 165.
    Costa M do C, Ashraf NS, Fischer S, Yang Y, Schapka E, Joshi G, et al. Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3. Brain. England; 2016;139:2891–908.CrossRefGoogle Scholar
  166. 166.
    Hubener J, Casadei N, Teismann P, Seeliger MW, Bjorkqvist M, von Horsten S, et al. Automated behavioral phenotyping reveals presymptomatic alterations in a SCA3 genetrap mouse model. J Genet Genomics. China; 2012;39:287–99.CrossRefGoogle Scholar
  167. 167.
    Rezende TJR, de Paiva JLR, Martinez ARM, Lopes-Cendes I, Pedroso JL, Barsottini OGP, et al. Structural signature of SCA3: From presymptomatic to late disease stages. Ann Neurol. United States; 2018;84:401–8.CrossRefGoogle Scholar
  168. 168.
    Rajamani K, Liu J-W, Wu C-H, Chiang I-T, You D-H, Lin S-Y, et al. n-Butylidenephthalide exhibits protection against neurotoxicity through regulation of tryptophan 2, 3 dioxygenase in spinocerebellar ataxia type 3. Neuropharmacology. England; 2017;117:434–46.CrossRefGoogle Scholar
  169. 169.
    Goncalves N, Simoes AT, Prediger RD, Hirai H, Cunha RA, Pereira de Almeida L. Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia. Ann Neurol. United States; 2017;81:407–18.Google Scholar
  170. 170.
    Esteves S, Oliveira S, Duarte-Silva S, Cunha-Garcia D, Teixeira-Castro A, Maciel P. Preclinical Evidence Supporting Early Initiation of Citalopram Treatment in Machado-Joseph Disease. Mol Neurobiol. United States; 2019;56:3626–37.CrossRefGoogle Scholar
  171. 171.
    Ashraf NS, Duarte-Silva S, Shaw ED, Maciel P, Paulson HL, Teixeira-Castro A, et al. Citalopram Reduces Aggregation of ATXN3 in a YAC Transgenic Mouse Model of Machado-Joseph Disease. Mol Neurobiol. United States; 2019;56:3690–701.CrossRefGoogle Scholar
  172. 172.
    Wang H-L, Hu S-H, Chou A-H, Wang S-S, Weng Y-H, Yeh T-H. 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. England; 2013;70:1–11.CrossRefGoogle Scholar
  173. 173.
    Chou A-H, Chen Y-L, Chiu C-C, Yuan S-J, Weng Y-H, Yeh T-H, et al. T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. Neuropharmacology. England; 2015;99:308–17.CrossRefGoogle Scholar
  174. 174.
    Duarte-Silva S, Maciel P. Pharmacological Therapies for Machado-Joseph Disease. Adv Exp Med Biol. United States; 2018;1049:369–94.CrossRefGoogle Scholar
  175. 175.
    Saute JAM, de Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, D’Avila R, et al. A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease. Mov Disord. United States; 2014;29:568–73.CrossRefGoogle Scholar
  176. 176.
    Schmidt J, Schmidt T, Golla M, Lehmann L, Weber JJ, Hubener-Schmid J, et al. In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3. J Neurochem. England; 2016;138:150–62.CrossRefGoogle Scholar
  177. 177.
    Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Prim. England; 2019;5:24.CrossRefGoogle Scholar
  178. 178.
    Matos CA, de Almeida LP, Nobrega C. Machado-Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy. J Neurochem. England; 2019;148:8–28.CrossRefGoogle Scholar
  179. 179.
    de Silva R, Greenfield J, Cook A, Bonney H, Vallortigara J, Hunt B, et al. Guidelines on the diagnosis and management of the progressive ataxias. Orphanet J Rare Dis. England; 2019;14:51.CrossRefGoogle Scholar
  180. 180.
    Council NH and MR. NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. NHMRC. NHMRC Canberra, Australia; 2009Google Scholar
  181. 181.
    van de Warrenburg BPC, van Gaalen J, Boesch S, Burgunder J-M, Durr A, Giunti P, et al. EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. Eur J Neurol. England; 2014;21:552–62.CrossRefGoogle Scholar
  182. 182.
    Zesiewicz TA, Greenstein PE, Sullivan KL, Wecker L, Miller A, Jahan I, et al. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology. United States; 2012;78:545–50.CrossRefGoogle Scholar
  183. 183.
    Paulson H. Machado-Joseph Disease/Spinocerebellar Ataxia Type 3. Handb Clin Neurol / Ed by PJ Vinken GW Bruyn. 2012;103:437–49.CrossRefGoogle Scholar
  184. 184.
    Riess O, Rüb U, Pastore A, Bauer P, Schöls L. SCA3: Neurological features, pathogenesis and animal models. The Cerebellum [Internet]. 2008;7:125–37. Available from:  https://doi.org/10.1007/s12311-008-0013-4 PubMedCrossRefGoogle Scholar
  185. 185.
    Sakai T, Antoku Y, Matsuishi T, Iwashita H. Tetrahydrobiopterin double-blind, crossover trial in Machado-Joseph disease. J Neurol Sci [Internet]. Elsevier; 1996;136:71–2. Available from:  https://doi.org/10.1016/0022-510X(95)00296-E PubMedCrossRefGoogle Scholar
  186. 186.
    Sakai T. Effects of tetrahydrobiopterin on ataxia in Machado-Joseph disease may be based upon the theory of “cerebellar long-term depression”. Med Hypotheses. United States; 2001;57:180–2.CrossRefGoogle Scholar
  187. 187.
    Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali M, et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. United States; 2010;74:839–45.CrossRefGoogle Scholar
  188. 188.
    Romano S, Coarelli G, Marcotulli C, Leonardi L, Piccolo F, Spadaro M, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. England; 2015;14:985–91.CrossRefGoogle Scholar
  189. 189.
    Takei A, Fukazawa T, Hamada T, Sohma H, Yabe I, Sasaki H, et al. Effects of tandospirone on “5-HT1A receptor-associated symptoms” in patients with Machado-Josephe disease: an open-label study. Clin Neuropharmacol. United States; 2004;27:9–13.CrossRefGoogle Scholar
  190. 190.
    Takei A, Hamada S, Homma S, Hamada K, Tashiro K, Hamada T. Difference in the effects of tandospirone on ataxia in various types of spinocerebellar degeneration: an open-label study. Cerebellum. United States; 2010;9:567–70.CrossRefGoogle Scholar
  191. 191.
    Sanz-Gallego I, Rodriguez-de-Rivera FJ, Pulido I, Torres-Aleman I, Arpa J. IGF-1 in autosomal dominant cerebellar ataxia - open-label trial. Cerebellum & ataxias. England; 2014;1:13.Google Scholar
  192. 192.
    Schulte T, Mattern R, Berger K, Szymanski S, Klotz P, Kraus PH, et al. Double-blind crossover trial of trimethoprim-sulfamethoxazole in spinocerebellar ataxia type 3/Machado-Joseph disease. Arch Neurol. United States; 2001;58:1451–7.CrossRefGoogle Scholar
  193. 193.
    Monte TL, Rieder CRM, Tort AB, Rockenback I, Pereira ML, Silveira I, et al. Use of fluoxetine for treatment of Machado-Joseph disease: an open-label study. Acta Neurol Scand. Denmark; 2003;107:207–10.CrossRefGoogle Scholar
  194. 194.
    Liu C-S, Hsu H-M, Cheng W-L, Hsieh M. Clinical and molecular events in patients with Machado-Joseph disease under lamotrigine therapy. Acta Neurol Scand. Denmark; 2005;111:385–90.CrossRefGoogle Scholar
  195. 195.
    Moeini-Naghani I, Hashemi-Zonouz T, Jabbari B. Botulinum Toxin Treatment of Spasticity in Adults and Children. Semin Neurol. United States; 2016;36:64–72.CrossRefGoogle Scholar
  196. 196.
    Lui J, Sarai M, Mills PB. Chemodenervation for treatment of limb spasticity following spinal cord injury: a systematic review. Spinal Cord. England; 2015;53:252–64.CrossRefGoogle Scholar
  197. 197.
    Berntsson SG, Gauffin H, Melberg A, Holtz A, Landtblom AM. Inherited Ataxia and Intrathecal Baclofen for the Treatment of Spasticity and Painful Spasms. Stereotact Funct Neurosurg. Switzerland; 2019;97:18–23.CrossRefGoogle Scholar
  198. 198.
    Delgado MR, Hirtz D, Aisen M, Ashwal S, Fehlings DL, McLaughlin J, et al. Practice parameter: pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child. Neurology. United States; 2010;74:336–43.CrossRefGoogle Scholar
  199. 199.
    Otero-Romero S, Sastre-Garriga J, Comi G, Hartung H-P, Soelberg Sorensen P, Thompson AJ, et al. Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper. Mult Scler. England; 2016;22:1386–96.CrossRefGoogle Scholar
  200. 200.
    Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology. United States; 1986;36:160–4.CrossRefGoogle Scholar
  201. 201.
    Ford B, Greene PE, Louis ED, Bressman SB, Goodman RR, Brin MF, et al. Intrathecal baclofen in the treatment of dystonia. Adv Neurol. United States; 1998;78:199–210.Google Scholar
  202. 202.
    Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind crossover study. Ann Neurol. United States; 1982;11:41–7.CrossRefGoogle Scholar
  203. 203.
    Hwang WJ, Calne DB, Tsui JK, de la Fuente-Fernandez R. The long-term response to levodopa in dopa-responsive dystonia. Parkinsonism Relat Disord. England; 2001;8:1–5.CrossRefGoogle Scholar
  204. 204.
    Simpson DM, Hallett M, Ashman EJ, Comella CL, Green MW, Gronseth GS, et al. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. United States; 2016;86:1818–26.CrossRefGoogle Scholar
  205. 205.
    Kanai K, Kuwabara S, Arai K, Sung J-Y, Ogawara K, Hattori T. Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain. England; 2003;126:965–73.CrossRefGoogle Scholar
  206. 206.
    Katzberg HD. Neurogenic muscle cramps. J Neurol. Germany; 2015;262:1814–21.CrossRefGoogle Scholar
  207. 207.
    Tuite PJ, Rogaeva EA, St George-Hyslop PH, Lang AE. Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion. Ann Neurol. United States; 1995;38:684–7.CrossRefGoogle Scholar
  208. 208.
    Nandagopal R, Moorthy SGK. Dramatic levodopa responsiveness of dystonia in a sporadic case of spinocerebellar ataxia type 3. Postgrad Med J. England; 2004;80:363–5.CrossRefGoogle Scholar
  209. 209.
    Bandini F, Castello E, Mazzella L, Mancardi GL, Solaro C. Gabapentin but not vigabatrin is effective in the treatment of acquired nystagmus in multiple sclerosis: How valid is the GABAergic hypothesis? J Neurol Neurosurg Psychiatry. England; 2001;71:107–10.CrossRefGoogle Scholar
  210. 210.
    Averbuch-Heller L, Tusa RJ, Fuhry L, Rottach KG, Ganser GL, Heide W, et al. A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus. Ann Neurol. United States; 1997;41:818–25.CrossRefGoogle Scholar
  211. 211.
    Mitchelson F. Pharmacological agents affecting emesis. A review (Part I). Drugs. New Zealand; 1992;43:295–315.Google Scholar
  212. 212.
    Venail F, Biboulet R, Mondain M, Uziel A. A protective effect of 5-HT3 antagonist against vestibular deficit? Metoclopramide versus ondansetron at the early stage of vestibular neuritis: a pilot study. Eur Ann Otorhinolaryngol Head Neck Dis. France; 2012;129:65–8.CrossRefGoogle Scholar
  213. 213.
    Soto E, Vega R, Sesena E. Neuropharmacological basis of vestibular system disorder treatment. J Vestib Res. Netherlands; 2013;23:119–37.Google Scholar
  214. 214.
    Curatolo M, Bogduk N. Pharmacologic pain treatment of musculoskeletal disorders: current perspectives and future prospects. Clin J Pain. United States; 2001;17:25–32.CrossRefGoogle Scholar
  215. 215.
    Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc. England; 2015;90:532–45.CrossRefGoogle Scholar
  216. 216.
    Sakakibara R, Panicker J, Finazzi-Agro E, Iacovelli V, Bruschini H. A guideline for the management of bladder dysfunction in Parkinson’s disease and other gait disorders. Neurourol Urodyn. United States; 2016;35:551–63.CrossRefGoogle Scholar
  217. 217.
    Bloom HG, Ahmed I, Alessi CA, Ancoli-Israel S, Buysse DJ, Kryger MH, et al. Evidence-based recommendations for the assessment and management of sleep disorders in older persons. J Am Geriatr Soc. United States; 2009;57:761–89.CrossRefGoogle Scholar
  218. 218.
    Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. United States; 2007;30:1705–11.CrossRefGoogle Scholar
  219. 219.
    Cecchin CR, Pires AP, Rieder CR, Monte TL, Silveira I, Carvalho T, et al. Depressive symptoms in Machado-Joseph disease (SCA3) patients and their relatives. Community Genet. Switzerland; 2007;10:19–26.CrossRefGoogle Scholar
  220. 220.
    Ilg W, Synofzik M, Brotz D, Burkard S, Giese MA, Schols L. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology. United States; 2009;73:1823–30.CrossRefGoogle Scholar
  221. 221.
    Miyai I, Ito M, Hattori N, Mihara M, Hatakenaka M, Yagura H, et al. Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases. Neurorehabil Neural Repair. United States; 2012;26:515–22.CrossRefGoogle Scholar
  222. 222.
    Wang R-Y, Huang F-Y, Soong B-W, Huang S-F, Yang Y-R. A randomized controlled pilot trial of game-based training in individuals with spinocerebellar ataxia type 3. Sci Rep. England; 2018;8:7816.CrossRefGoogle Scholar
  223. 223.
    Walsh T, Petrie H. Understanding the Lived Experience of Five Individuals with Mobility Aids. Stud Health Technol Inform. Netherlands; 2016;229:582–93.Google Scholar
  224. 224.
    Maas E, Robin DA, Austermann Hula SN, Freedman SE, Wulf G, Ballard KJ, et al. Principles of motor learning in treatment of motor speech disorders. Am J speech-language Pathol. United States; 2008;17:277–98.Google Scholar
  225. 225.
    Vogel AP, Folker J, Poole ML. Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes. Cochrane database Syst Rev. England; 2014;CD008953.Google Scholar
  226. 226.
    Gallegos C, Brito-de la Fuente E, Clave P, Costa A, Assegehegn G. Nutritional Aspects of Dysphagia Management. Adv Food Nutr Res. United States; 2017;81:271–318.CrossRefGoogle Scholar
  227. 227.
    Silva RCR, Saute JAM, Silva ACF, Coutinho ACO, Saraiva-Pereira ML, Jardim LB. Occupational therapy in spinocerebellar ataxia type 3: an open-label trial. Brazilian J Med Biol Res = Rev Bras Pesqui medicas e Biol. Brazil; 2010;43:537–42.CrossRefGoogle Scholar
  228. 228.
    Fonteyn EMR, Keus SHJ, Verstappen CCP, Schols L, de Groot IJM, van de Warrenburg BPC. The effectiveness of allied health care in patients with ataxia: a systematic review. J Neurol. Germany; 2014;261:251–8.CrossRefGoogle Scholar
  229. 229.
    Sukkay S. Multidisciplinary Procedures for Designing Housing Adaptations for People with Mobility Disabilities. Stud Health Technol Inform. Netherlands; 2016;229:355–62.Google Scholar
  230. 230.
    Pirker W, Back C, Gerschlager W, Laccone F, Alesch F. Chronic thalamic stimulation in a patient with spinocerebellar ataxia type 2. Mov Disord. United States; 2003;18:222–5.CrossRefGoogle Scholar
  231. 231.
    Blomstedt P, Sandvik U, Tisch S. Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor. Mov Disord. United States; 2010;25:1350–6.CrossRefGoogle Scholar
  232. 232.
    Nahm NJ, Graham HK, Gormley MEJ, Georgiadis AG. Management of hypertonia in cerebral palsy. Curr Opin Pediatr. United States; 2018;30:57–64.CrossRefGoogle Scholar
  233. 233.
    Toh Yoon EW, Hirao J, Minoda N. Outcome of Rehabilitation and Swallowing Therapy after Percutaneous Endoscopic Gastrostomy in Dysphagia Patients. Dysphagia. United States; 2016;31:730–6.CrossRefGoogle Scholar
  234. 234.
    Saute JAM, Jardim LB. Planning Future Clinical Trials for Machado-Joseph Disease. Adv Exp Med Biol. United States; 2018;1049:321–48.CrossRefGoogle Scholar
  235. 235.
    Lei L-F, Yang G-P, Wang J-L, Chuang D-M, Song W-H, Tang B-S, et al. Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord. England; 2016;26:55–61.CrossRefGoogle Scholar
  236. 236.
    Lin C-H, Wu Y-R, Yang J-M, Chen W-L, Chao C-Y, Chen I-C, et al. Novel Lactulose and Melibiose Targeting Autophagy to Reduce PolyQ Aggregation in Cell Models of Spinocerebellar Ataxia 3. CNS Neurol Disord Drug Targets. United Arab Emirates; 2016;15:351–9.Google Scholar
  237. 237.
    Kempf L, Goldsmith JC, Temple R. Challenges of developing and conducting clinical trials in rare disorders. Am J Med Genet A. United States; 2018;176:773–83.CrossRefGoogle Scholar
  238. 238.
    Le TT. Incentivizing Orphan Product Development: United States Food and Drug Administration Orphan Incentive Programs. Adv Exp Med Biol. United States; 2017;1031:183–96.CrossRefGoogle Scholar
  239. 239.
    Richter T, Nestler-Parr S, Babela R, Khan ZM, Tesoro T, Molsen E, et al. Rare Disease Terminology and Definitions-A Systematic Global Review: Report of the ISPOR Rare Disease Special Interest Group. Value Heal J Int Soc Pharmacoeconomics Outcomes Res. United States; 2015;18:906–14.CrossRefGoogle Scholar
  240. 240.
    Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. Switzerland; 2014;42:174–83.CrossRefGoogle Scholar
  241. 241.
    Haffner ME. History of Orphan Drug Regulation-United States and Beyond. Clin Pharmacol Ther. United States; 2016;100:342–3.CrossRefGoogle Scholar
  242. 242.
    Westermark K, Holm BB, Soderholm M, Llinares-Garcia J, Riviere F, Aarum S, et al. European regulation on orphan medicinal products: 10 years of experience and future perspectives. Nat. Rev. Drug Discov. England; 2011. p. 341–9.Google Scholar
  243. 243.
    Jacobi H, Bauer P, Giunti P, Labrum R, Sweeney MG, Charles P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology. United States; 2011;77:1035–41.CrossRefGoogle Scholar
  244. 244.
    Jacobi H, du Montcel ST, Bauer P, Giunti P, Cook A, Labrum R, et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. England; 2015;14:1101–8.CrossRefGoogle Scholar
  245. 245.
    Subramony SH, Hernandez D, Adam A, Smith-Jefferson S, Hussey J, Gwinn-Hardy K, et al. Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians. Mov Disord. United States; 2002;17:1068–71.CrossRefGoogle Scholar
  246. 246.
    Saute JAM, Rieder CRM, Castilhos RM, Monte TL, Schumacher-Schuh AF, Donis KC, et al. Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial. J Neurol Sci. Netherlands; 2015;358:72–6.CrossRefGoogle Scholar
  247. 247.
    Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. United States; 2006;66:1717–20.CrossRefGoogle Scholar
  248. 248.
    Storey E, Tuck K, Hester R, Hughes A, Churchyard A. Inter-rater reliability of the International Cooperative Ataxia Rating Scale (ICARS). Mov Disord. United States; 2004;19:190–2.CrossRefGoogle Scholar
  249. 249.
    Brandsma R, Lawerman TF, Kuiper MJ, Lunsing RJ, Burger H, Sival DA. Reliability and discriminant validity of ataxia rating scales in early onset ataxia. Dev Med Child Neurol. England; 2017;59:427–32.CrossRefGoogle Scholar
  250. 250.
    Lawerman TF, Brandsma R, Verbeek RJ, van der Hoeven JH, Lunsing RJ, Kremer HPH, et al. Construct Validity and Reliability of the SARA Gait and Posture Sub-scale in Early Onset Ataxia. Front Hum Neurosci. Switzerland; 2017;11:605.CrossRefGoogle Scholar
  251. 251.
    Salci Y, Fil A, Keklicek H, Cetin B, Armutlu K, Dolgun A, et al. Validity and reliability of the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and Rating of Ataxia (SARA) in multiple sclerosis patients with ataxia. Mult Scler Relat Disord. Netherlands; 2017;18:135–40.CrossRefGoogle Scholar
  252. 252.
    Tan S, Niu H, Zhao L, Gao Y, Lu J, Shi C, et al. Reliability and validity of the Chinese version of the Scale for Assessment and Rating of Ataxia. Chin Med J (Engl). China; 2013;126:2045–8.Google Scholar
  253. 253.
    Braga-Neto P, Godeiro-Junior C, Dutra LA, Pedroso JL, Barsottini OGP. Translation and validation into Brazilian version of the Scale of the Assessment and Rating of Ataxia (SARA). Arq Neuropsiquiatr. Brazil; 2010;68:228–30.CrossRefGoogle Scholar
  254. 254.
    Weyer A, Abele M, Schmitz-Hubsch T, Schoch B, Frings M, Timmann D, et al. Reliability and validity of the scale for the assessment and rating of ataxia: a study in 64 ataxia patients. Mov Disord. United States; 2007;22:1633–7.CrossRefGoogle Scholar
  255. 255.
    Yuan X, Ou R, Hou Y, Chen X, Cao B, Hu X, et al. Extra-Cerebellar Signs and Non-motor Features in Chinese Patients With Spinocerebellar Ataxia Type 3. Front Neurol. Switzerland; 2019;10:110.CrossRefGoogle Scholar
  256. 256.
    Hee SW, Willis A, Tudur Smith C, Day S, Miller F, Madan J, et al. Does the low prevalence affect the sample size of interventional clinical trials of rare diseases? An analysis of data from the aggregate analysis of clinicaltrials.gov. Orphanet J Rare Dis. England; 2017;12:44.CrossRefGoogle Scholar
  257. 257.
    Lagakos SW. Clinical trials and rare diseases. N. Engl. J. Med. United States; 2003. p. 2455–6.Google Scholar
  258. 258.
    Evans CH, Ildstad ST. Small Clinical Trials. Issues and Challenges. 2001Google Scholar
  259. 259.
    Meeker-O’Connell A, Glessner C, Behm M, Mulinde J, Roach N, Sweeney F, et al. Enhancing clinical evidence by proactively building quality into clinical trials. Clin Trials. SAGE Publications Sage UK: London, England; 2016;13:439–44.Google Scholar
  260. 260.
    Bushart DD, Murphy GG, Shakkottai VG. Precision medicine in spinocerebellar ataxias: treatment based on common mechanisms of disease. Ann Transl Med. AME Publications; 2016;4.Google Scholar
  261. 261.
    Rueb U, Schoels L, Paulson H, Auburger G, Kermer P, Jen JC, et al. Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog Neurobiol. Elsevier; 2013;104:38–66.CrossRefGoogle Scholar
  262. 262.
    Davies SW, Beardsall K, Turmaine M, DiFiglia M, Aronin N, Bates GP. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions? Lancet. Elsevier; 1998;351:131–3.Google Scholar
  263. 263.
    Patel MM, Patel BM. Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain. CNS Drugs. New Zealand; 2017;31:109–33.CrossRefGoogle Scholar
  264. 264.
    Mendes A, Paneque M, Clarke A, Sequeiros J. Choosing not to know: accounts of non-engagement with pre-symptomatic testing for Machado-Joseph disease. Eur J Hum Genet. England; 2019;27:353–9.CrossRefGoogle Scholar
  265. 265.
    Novac N. Challenges and opportunities of drug repositioning. Trends Pharmacol Sci. England; 2013;34:267–72.CrossRefGoogle Scholar
  266. 266.
    Cha Y, Erez T, Reynolds IJ, Kumar D, Ross J, Koytiger G, et al. Drug repurposing from the perspective of pharmaceutical companies. Br J Pharmacol. England; 2018;175:168–80.CrossRefGoogle Scholar
  267. 267.
    Beaumont R, Cordery P, Funnell M, Mears S, James L, Watson P. Chronic ingestion of a low dose of caffeine induces tolerance to the performance benefits of caffeine. J Sports Sci. England; 2017;35:1920–7.CrossRefGoogle Scholar
  268. 268.
    Bezchlibnyk-Butler K, Aleksic I, Kennedy SH. Citalopram—a review of pharmacological and clinical effects. J Psychiatry Neurosci. Canadian Medical Association; 2000;25:241.Google Scholar
  269. 269.
    Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene—a review of its pharmacology, therapeutic use and new developments. Anaesthesia. England; 2004;59:364–73.CrossRefGoogle Scholar
  270. 270.
    Soulieres D. Side-effects associated with targeted therapies in renal cell carcinoma. Curr Opin Support Palliat Care. United States; 2013;7:254–7.CrossRefGoogle Scholar
  271. 271.
    Kalra EK. Nutraceutical-definition and introduction. AAPS PharmSci. Springer; 2003;5:27–8.CrossRefGoogle Scholar
  272. 272.
    Paller CJ, Denmeade SR, Carducci MA. Challenges of conducting clinical trials of natural products to combat cancer. Clin Adv Hematol Oncol. 2016;14:447–55.PubMedGoogle Scholar
  273. 273.
    Dwyer J, Coates P, Smith M. Dietary supplements: regulatory challenges and research resources. Nutrients. Multidisciplinary Digital Publishing Institute; 2018;10:41.Google Scholar
  274. 274.
    Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. ASPET; 2001;53:161–76.Google Scholar
  275. 275.
    Subramanian L, Youssef S, Bhattacharya S, Kenealey J, Polans AS, van Ginkel PR. Resveratrol: challenges in translation to the clinic—a critical discussion. Clin Cancer Res. AACR; 2010;16:5942–8.CrossRefGoogle Scholar
  276. 276.
    Holzbeierlein JM, Windsperger A, Vielhauer G. Hsp90: a drug target? Curr Oncol Rep. Springer; 2010;12:95–101.Google Scholar
  277. 277.
    Garber K. HDAC inhibitors overcome first hurdle. Nature Publishing Group; 2007.Google Scholar
  278. 278.
    Wang Z. Experimental and Clinical Strategies for Treating Spinocerebellar Ataxia Type 3. Neuroscience. United States; 2018;371:138–54.Google Scholar
  279. 279.
    Chiriboga CA. Nusinersen for the treatment of spinal muscular atrophy. Expert Rev Neurother. England; 2017;17:955–62.CrossRefGoogle Scholar
  280. 280.
    McLoughlin HS, Moore LR, Chopra R, Komlo R, McKenzie M, Blumenstein KG, et al. Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann Neurol. United States; 2018;84:64–77.CrossRefGoogle Scholar
  281. 281.
    Moore LR, Rajpal G, Dillingham IT, Qutob M, Blumenstein KG, Gattis D, et al. Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models. Mol Ther Nucleic Acids. United States; 2017;7:200–10.CrossRefGoogle Scholar
  282. 282.
    Zeng L, Zhang D, McLoughlin HS, Zalon AJ, Aravind L, Paulson HL. Loss of the Spinocerebellar Ataxia type 3 disease protein ATXN3 alters transcription of multiple signal transduction pathways. PLoS One. United States; 2018;13:e0204438.CrossRefGoogle Scholar
  283. 283.
    Alves S, Nascimento-Ferreira I, Dufour N, Hassig R, Auregan G, Nobrega C, et al. Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3? Hum Mol Genet. England; 2010;19:2380–94.CrossRefGoogle Scholar
  284. 284.
    Nobrega C, Codesso JM, Mendonca L, Pereira de Almeida L. RNA Interference Therapy for Machado-Joseph Disease: Long-Term Safety Profile of Lentiviral Vectors Encoding Short Hairpin RNAs Targeting Mutant Ataxin-3. Hum Gene Ther. United States; 2019Google Scholar
  285. 285.
    Baum C, Düllmann J, Li Z, Fehse B, Meyer J, Williams DA, et al. Side effects of retroviral gene transfer into hematopoietic stem cells. Blood. Am Soc Hematology; 2003;101:2099–113.Google Scholar
  286. 286.
    McGarrity GJ, Hoyah G, Winemiller A, Andre K, Stein D, Blick G, et al. Patient monitoring and follow-up in lentiviral clinical trials. J Gene Med. Wiley Online Library; 2013;15:78–82.Google Scholar
  287. 287.
    Wong L-F, Goodhead L, Prat C, Mitrophanous KA, Kingsman SM, Mazarakis ND. Lentivirus-mediated gene transfer to the central nervous system: therapeutic and research applications. Hum Gene Ther. Mary Ann Liebert, Inc. 2 Madison Avenue Larchmont, NY 10538 USA; 2006;17:1–9.Google Scholar
  288. 288.
    Jakobsson J, Lundberg C. Lentiviral vectors for use in the central nervous system. Mol Ther. Elsevier; 2006;13:484–93.CrossRefGoogle Scholar
  289. 289.
    Ouyang S, Xie Y, Xiong Z, Yang Y, Xian Y, Ou Z, et al. CRISPR/Cas9-Targeted Deletion of Polyglutamine in Spinocerebellar Ataxia Type 3-Derived Induced Pluripotent Stem Cells. Stem Cells Dev. United States; 2018;27:756–70.CrossRefGoogle Scholar
  290. 290.
    Aymé S, Kole A, Groft S. Empowerment of patients: lessons from the rare diseases community. Lancet. Elsevier; 2008;371:2048–51.CrossRefGoogle Scholar
  291. 291.
    Budych K, Helms TM, Schultz C. How do patients with rare diseases experience the medical encounter? Exploring role behavior and its impact on patient–physician interaction. Health Policy (New York). Elsevier; 2012;105:154–64.Google Scholar
  292. 292.
    Garrino L, Picco E, Finiguerra I, Rossi D, Simone P, Roccatello D. Living with and treating rare diseases: experiences of patients and professional health care providers. Qual Health Res. United States; 2015;25:636–51.CrossRefGoogle Scholar
  293. 293.
    Pulciani S, Nutile E, Taruscio D. Patient Associations: a driving force for Rare Diseases research. Resilience: a driving force for Patient Associations. Ann Ig. Italy; 2018;30:307–16.Google Scholar
  294. 294.
    Forsythe LP, Szydlowski V, Murad MH, Ip S, Wang Z, Elraiyah TA, et al. A systematic review of approaches for engaging patients for research on rare diseases. J Gen Intern Med. Springer; 2014;29:788–800.CrossRefGoogle Scholar
  295. 295.
    Castillo-Esparcia A, Lopez-Villafranca P. Communication strategies employed by rare disease patient organizations in Spain. Cien Saude Colet. Brazil; 2016;21:2423–36.CrossRefGoogle Scholar
  296. 296.
    Landy DC, Brinich MA, Colten ME, Horn EJ, Terry SF, Sharp RR. How disease advocacy organizations participate in clinical research: a survey of genetic organizations. Genet Med. Nature Publishing Group; 2012;14:223.Google Scholar
  297. 297.
    Huyard C. What, if anything, is specific about having a rare disorder? Patients’ judgements on being ill and being rare. Heal Expect. Wiley Online Library; 2009;12:361–70.CrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  • Jorge Diogo Da Silva
    • 1
    • 2
  • Andreia Teixeira-Castro
    • 1
    • 2
  • Patrícia Maciel
    • 1
    • 2
    Email author
  1. 1.Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
  2. 2.ICVS/3B’s - PT Government Associate LaboratoryBraga/GuimarãesPortugal

Personalised recommendations