Pharmacological Therapies for Machado-Joseph Disease

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1049)


Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia type 3 (SCA3), is the most common autosomal dominant ataxia worldwide. MJD integrates a large group of disorders known as polyglutamine diseases (polyQ). To date, no effective treatment exists for MJD and other polyQ diseases. Nevertheless, researchers are making efforts to find treatment possibilities that modify the disease course or alleviate disease symptoms. Since neuroimaging studies in mutation carrying individuals suggest that in nervous system dysfunction begins many years before the onset of any detectable symptoms, the development of therapeutic interventions becomes of great importance, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset. Potential therapeutic targets for MJD and polyQ diseases can be divided into (i) those that are aimed at the polyQ proteins themselves, namely gene silencing, attempts to enhance mutant protein degradation or inhibition/prevention of aggregation; and (ii) those that intercept the toxic downstream effects of the polyQ proteins, such as mitochondrial dysfunction and oxidative stress, transcriptional abnormalities, UPS impairment, excitotoxicity, or activation of cell death. The existence of relevant animal models and the recent contributions towards the identification of putative molecular mechanisms underlying MJD are impacting on the development of new drugs. To date only a few preclinical trials were conducted, nevertheless some had very promising results and some candidate drugs are close to being tested in humans. Clinical trials for MJD are also very few to date and their results not very promising, mostly due to trial design constraints. Here, we provide an overview of the pharmacological therapeutic strategies for MJD studied in animal models and patients, and of their possible translation into the clinical practice.


PolyQ diseases Machado-Joseph disease Pharmacologic therapy 


  1. 1.
    Paulson H (2012) Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol 103:437–449Google Scholar
  2. 2.
    Bettencourt C, Lima M (2011) Machado-Joseph disease: from first descriptions to new perspectives. Orphanet J Rare Dis 6:35Google Scholar
  3. 3.
    Matos CA, de Macedo-Ribeiro S, Carvalho AL (2011) Polyglutamine diseases: the special case of ataxin-3 and Machado-Joseph disease. Prog Neurobiol 95(1):26–48CrossRefPubMedGoogle Scholar
  4. 4.
    Schols L, Bauer P, Schmidt T, Schulte T, Riess O (2004) Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 3(5):291–304CrossRefPubMedGoogle Scholar
  5. 5.
    Switonski PM, Szlachcic WJ, Gabka A, Krzyzosiak WJ, Figiel M (2012) Mouse models of polyglutamine diseases in therapeutic approaches: review and data table. Part II. Mol Neurobiol 46(2):430–466CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bauer PO, Nukina N (2009) The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. J Neurochem 110(6):1737–1765CrossRefPubMedGoogle Scholar
  7. 7.
    Saute JAM, Jardim LB (2015) Machado Joseph disease: clinical and genetic aspects, and current treatment. Expert Opin Orphan Drugs 3(5):517–535CrossRefGoogle Scholar
  8. 8.
    Coutinho P, Sequeiros J (1981) Clinical, genetic and pathological aspects of Machado-Joseph disease. J Genet Hum 29(3):203–209PubMedGoogle Scholar
  9. 9.
    Riess O, Rub U, Pastore A, Bauer P, Schols L (2008) SCA3: neurological features, pathogenesis and animal models. Cerebellum 7(2):125–137CrossRefPubMedGoogle Scholar
  10. 10.
    Rosenberg RN (1992) Machado-Joseph disease: an autosomal dominant motor system degeneration. Mov Disord 7(3):193–203CrossRefPubMedGoogle Scholar
  11. 11.
    Rub U, Brunt ER, Deller T (2008) New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease). Curr Opin Neurol 21(2):111–116CrossRefPubMedGoogle Scholar
  12. 12.
    Franca MC Jr, D’Abreu A, Nucci A, Lopes-Cendes I (2008) Muscle excitability abnormalities in Machado-Joseph disease. Arch Neurol 65(4):525–529CrossRefPubMedGoogle Scholar
  13. 13.
    Friedman JH, Amick MM (2008) Fatigue and daytime somnolence in Machado Joseph disease (spinocerebellar ataxia type 3). Mov Disord 23(9):1323–1324CrossRefPubMedGoogle Scholar
  14. 14.
    Schols L, Haan J, Riess O, Amoiridis G, Przuntek H (1998) Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome? Neurology 51(6):1603–1607CrossRefPubMedGoogle Scholar
  15. 15.
    Kawai Y, Takeda A, Abe Y, Washimi Y, Tanaka F, Sobue G (2004) Cognitive impairments in Machado-Joseph disease. Arch Neurol 61(11):1757–1760CrossRefPubMedGoogle Scholar
  16. 16.
    Silva UC, Marques W Jr, Lourenco CM, Hallak JE, Osorio FL (2015) Psychiatric disorders, spinocerebellar ataxia type 3 and CAG expansion. J Neurol 262(7):1777–1779CrossRefPubMedGoogle Scholar
  17. 17.
    Paulson HL, Perez MK, Trottier Y, et al (1997) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19(2):333–344CrossRefPubMedGoogle Scholar
  18. 18.
    Schmidt T, Landwehrmeyer GB, Schmitt I, et al (1998) An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 8(4):669–679CrossRefPubMedGoogle Scholar
  19. 19.
    Rub U, Seidel K, Ozerden I, et al (2007) Consistent affection of the central somatosensory system in spinocerebellar ataxia type 2 and type 3 and its significance for clinical symptoms and rehabilitative therapy. Brain Res Rev 53(2):235–249CrossRefPubMedGoogle Scholar
  20. 20.
    Yamada M, Tan CF, Inenaga C, Tsuji S, Takahashi H (2004) Sharing of polyglutamine localization by the neuronal nucleus and cytoplasm in CAG-repeat diseases. Neuropathol Appl Neurobiol 30(6):665–675CrossRefPubMedGoogle Scholar
  21. 21.
    Seidel K, den Dunnen WF, Schultz C, et al (2010) Axonal inclusions in spinocerebellar ataxia type 3. Acta Neuropathol 120(4):449–460CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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(7):703–709CrossRefPubMedGoogle Scholar
  23. 23.
    Lima L, Coutinho P (1980) Clinical criteria for diagnosis of Machado-Joseph disease: report of a non-Azoren Portuguese family. Neurology 30(3):319–322Google Scholar
  24. 24.
    Paulson H (1993). Spinocerebellar ataxia type 3. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews(R). Seattle, WAGoogle Scholar
  25. 25.
    Maciel P, Costa MC, Ferro A, et al (2001) Improvement in the molecular diagnosis of Machado-Joseph disease. Arch Neurol 58(11):1821–1827CrossRefPubMedGoogle Scholar
  26. 26.
    Rodrigues CS, de Oliveira VZ, Camargo G, et al (2012) Presymptomatic testing for neurogenetic diseases in Brazil: assessing who seeks and who follows through with testing. J genet couns 21(1):101–112Google Scholar
  27. 27.
    Miyai I, Ito M, Hattori N, et al (2012) Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases. Neurorehabil Neural Repair 26(5):515–522Google Scholar
  28. 28.
    Svensson M, Lexell J, Deierborg T (2015) Effects of physical exercise on neuroinflammation, neuroplasticity, neurodegeneration, and behavior: what we can learn from animal models in clinical settings. Neurorehabil Neural Repair 29(6):577–589Google Scholar
  29. 29.
    Silva RC, Saute JA, Silva AC, Coutinho AC, Saraiva-Pereira ML, Jardim LB (2010) Occupational therapy in spinocerebellar ataxia type 3: an open-label trial. Braz J Med Biol Res = Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica [et al] 43(6):537–542CrossRefPubMedGoogle Scholar
  30. 30.
    Cecchin CR, Pires AP, Rieder CR, et al (2007) Depressive symptoms in Machado-Joseph disease (SCA3) patients and their relatives. Commun Genet 10(1):19–26CrossRefGoogle Scholar
  31. 31.
    Nandagopal R, Moorthy SG (2004) Dramatic levodopa responsiveness of dystonia in a sporadic case of spinocerebellar ataxia type 3. Postgrad Med J 80(944):363–365CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Thanvi B, Lo N, Robinson T (2007) Levodopa-induced dyskinesia in Parkinson’s disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J 83(980):384–388CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    D’Abreu A, Franca MC Jr, Paulson HL, Lopes-Cendes I (2010) Caring for Machado-Joseph disease: current understanding and how to help patients. Parkinsonism Relat Disord 16(1):2–7CrossRefPubMedGoogle Scholar
  34. 34.
    Szlachcic WJ, Switonski PM, Kurkowiak M, Wiatr K, Figiel M (2015) Mouse polyQ database: a new online resource for research using mouse models of neurodegenerative diseases. Mol Brain 8(1):69CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Colomer Gould VF (2012) Mouse models of spinocerebellar ataxia type 3 (Machado-Joseph disease). Neurotherapeutics 9(2):285–296CrossRefGoogle Scholar
  36. 36.
    Whitesell L, Bagatell R, Falsey R (2003) The stress response: implications for the clinical development of hsp90 inhibitors. Curr Cancer Drug Targets 3(5):349–358CrossRefPubMedGoogle Scholar
  37. 37.
    Bagatell R, Paine-Murrieta GD, Taylor CW, et al (2000) Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of hsp90-binding agents. Clin Cancer Res 6(8):3312–3318PubMedGoogle Scholar
  38. 38.
    Fujikake N, Nagai Y, Popiel HA, Okamoto Y, Yamaguchi M, Toda T (2008) Heat shock transcription factor 1-activating compounds suppress polyglutamine-induced neurodegeneration through induction of multiple molecular chaperones. J Biol Chem 283(38):26188–26197CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Tokui K, Adachi H, Waza M, et al (2009) 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse. Hum Mol Genet 18(5):898–910Google Scholar
  40. 40.
    Waza M, Adachi H, Katsuno M, et al (2005) 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med 11(10):1088–1095CrossRefPubMedGoogle Scholar
  41. 41.
    Thomas M, Harrell JM, Morishima Y, Peng HM, Pratt WB, Lieberman AP (2006) Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction. Hum Mol Genet 15(11):1876–1883CrossRefPubMedGoogle Scholar
  42. 42.
    Silva-Fernandes A, Duarte-Silva S, Neves-Carvalho A, et al (2014) Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease. Neurother: j Am Soc Exp NeuroTher 11(2):433–449Google Scholar
  43. 43.
    Jhaveri K, Taldone T, Modi S, Chiosis G (2012) Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 1823(3):742–755CrossRefPubMedGoogle Scholar
  44. 44.
    del Cano-Espinel M, Acebes JR, Sanchez D, Ganfornina MD (2015) Lazarillo-related Lipocalins confer long-term protection against type I Spinocerebellar ataxia degeneration contributing to optimize selective autophagy. Mol Neurodegeneration 10:11CrossRefGoogle Scholar
  45. 45.
    Menzies FM, Garcia-Arencibia M, Imarisio S, et al (2015) Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity. Cell Death Differ 22(3):433–444CrossRefPubMedGoogle Scholar
  46. 46.
    Tsunemi T, Ashe TD, Morrison BE, et al (2012) PGC-1alpha rescues Huntington’s disease proteotoxicity by preventing oxidative stress and promoting TFEB function. Sci Transl Med 4(142):142–197Google Scholar
  47. 47.
    Roscic A, Baldo B, Crochemore C, Marcellin D, Paganetti P (2011) Induction of autophagy with catalytic mTOR inhibitors reduces huntingtin aggregates in a neuronal cell model. J Neurochem 119(2):398–407CrossRefPubMedGoogle Scholar
  48. 48.
    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 : J neurol 133(Pt 1):93–104CrossRefGoogle Scholar
  49. 49.
    Sarkar S, Krishna G, Imarisio S, Saiki S, O’Kane CJ, Rubinsztein DC (2008) A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum Mol Genet 17(2):170–178CrossRefPubMedGoogle Scholar
  50. 50.
    Williams A, Jahreiss L, Sarkar S, et al (2006) Aggregate-prone proteins are cleared from the cytosol by autophagy: therapeutic implications. Curr Top Dev Biol 76:89–101CrossRefPubMedGoogle Scholar
  51. 51.
    Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11(9):1107–1117CrossRefPubMedGoogle Scholar
  52. 52.
    Ravikumar B, Vacher C, Berger Z, et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36(6):585–595CrossRefPubMedGoogle Scholar
  53. 53.
    Xilouri M, Stefanis L (2015) Chaperone mediated autophagy to the rescue: a new-fangled target for the treatment of neurodegenerative diseases. Mol Cell Neurosci 66(Pt A):29–36Google Scholar
  54. 54.
    Frake RA, Ricketts T, Menzies FM, Rubinsztein DC (2015) Autophagy and neurodegeneration. J Clin Invest 125(1):65–74CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Harris H, Rubinsztein DC (2012) Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol 8(2):108–117CrossRefGoogle Scholar
  56. 56.
    Cortes CJ, La Spada AR (2015) Autophagy in polyglutamine disease: imposing order on disorder or contributing to the chaos? Mol Cell Neurosci 66(Pt A): 53–61Google Scholar
  57. 57.
    Bichelmeier U, Schmidt T, Hubener J, et al (2007) Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci: Official J Soc Neurosci 27(28):7418–7428CrossRefGoogle Scholar
  58. 58.
    Nascimento-Ferreira I, Santos-Ferreira T, Sousa-Ferreira L, et al (2011) Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease. Brain: J neurol 134(Pt 5):1400–1415CrossRefGoogle Scholar
  59. 59.
    Duarte-Silva S, Neves-Carvalho A, Soares-Cunha C, et al (2014) Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease. Cerebellum 13(6):713–727CrossRefPubMedGoogle Scholar
  60. 60.
    Saute JA, de Castilhos RM, Monte TL, et al (2014) A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease. Mov Disord 29(4):568–573CrossRefPubMedGoogle Scholar
  61. 61.
    Duarte-Silva S, Silva-Fernandes A, Neves-Carvalho A, Soares-Cunha C, Teixeira-Castro A, Maciel P (2016) Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease. Neuroscience 313:162–173Google Scholar
  62. 62.
    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(1):89–101CrossRefPubMedGoogle Scholar
  63. 63.
    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 70:1–11Google Scholar
  64. 64.
    Mueller BK, Mack H, Teusch N (2005) Rho kinase, a promising drug target for neurological disorders. Nat Rev Drug Discov 4(5):387–398CrossRefPubMedGoogle Scholar
  65. 65.
    Li M, Huang Y, Ma AA, Lin E, Diamond MI (2009) Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice. Neurobiol Dis 36(3):413–420CrossRefPubMedGoogle Scholar
  66. 66.
    Zhao J, Zhou D, Guo J, et al (2006) Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage. Neurol Med Chir 46(9):421–428CrossRefGoogle Scholar
  67. 67.
    Ahmed LA, Darwish HA, Abdelsalam RM, Amin HA (2015) Role of Rho kinase inhibition in the protective effect of Fasudil and Simvastatin against 3-Nitropropionic acid-induced striatal neurodegeneration and mitochondrial dysfunction in Rats. Mol NeurobiolGoogle Scholar
  68. 68.
    Lin Y, Hubert L Jr, Wilson JH (2009) Transcription destabilizes triplet repeats. Mol Carcinog 48(4):350–361CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Okazawa H (2003) Polyglutamine diseases: a transcription disorder? Cell Mol Life Sci 60(7):1427–1439CrossRefPubMedGoogle Scholar
  70. 70.
    McCampbell A, Taylor JP, Taye AA, et al (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9(14):2197–2202CrossRefPubMedGoogle Scholar
  71. 71.
    Taylor JP, Taye AA, Campbell C, Kazemi-Esfarjani P, Fischbeck KH, Min KT (2003) Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev 17(12):1463–1468CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    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(47):45004–45012CrossRefPubMedGoogle Scholar
  73. 73.
    Li SH, Cheng AL, Zhou H, et al (2002) Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 22(5):1277–1287CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Cohen-Carmon D, Meshorer E (2012) Polyglutamine (polyQ) disorders: the chromatin connection. Nucleus 3(5):433–441CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Chai Y, Wu L, Griffin JD, Paulson HL (2001) The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease. J Biol Chem 276(48):44889–44897CrossRefPubMedGoogle Scholar
  76. 76.
    Dunah AW, Jeong H, Griffin A, et al (2002) Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296(5576):2238–2243CrossRefPubMedGoogle Scholar
  77. 77.
    Grewal SI, Moazed D (2003) Heterochromatin and epigenetic control of gene expression. Science 301(5634):798–802CrossRefPubMedGoogle Scholar
  78. 78.
    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(2):481–488CrossRefPubMedGoogle Scholar
  79. 79.
    Esteves S, Duarte-Silva S, Naia L, et al (2015) Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph disease. PloS one 10(10):e0141610Google Scholar
  80. 80.
    Tang TS, Tu H, Chan EY, et al (2003) Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39(2):227–239CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Tang TS, Slow E, Lupu V, et al (2005) Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington’s disease. Proc Natl Acad Sci USA 102(7):2602–2607CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Wu J, Tang T, Bezprozvanny I (2006) Evaluation of clinically relevant glutamate pathway inhibitors in in vitro model of Huntington’s disease. Neurosci Lett 407(3):219–223CrossRefPubMedGoogle Scholar
  83. 83.
    Cemal CK, Carroll CJ, Lawrence L, et al (2002) YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit. Hum mol genet 11(9):1075–1094Google Scholar
  84. 84.
    Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (2004) Dantrolene–a review of its pharmacology, therapeutic use and new developments. Anaesthesia 59(4):364–373CrossRefPubMedGoogle Scholar
  85. 85.
    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 48:12713–12724Google Scholar
  86. 86.
    Stutzmann GE (2005) Calcium dysregulation, IP3 signaling, and Alzheimer’s disease. Neuroscientist: Rev J Bringing Neurobiol, Neurol Psychiatry 11(2):110–115CrossRefGoogle Scholar
  87. 87.
    Andrews TC, Weeks RA, Turjanski N, et al (1999) Huntington’s disease progression. PET and clinical observations. Brain: J Neurol 122(Pt 12):2353-2363Google Scholar
  88. 88.
    Li H, Li SH, Yu ZX, Shelbourne P, Li XJ (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington’s disease mice. J Neurosci: Official J Soc Neurosci 21(21):8473–8481Google Scholar
  89. 89.
    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(5):655–666Google Scholar
  90. 90.
    Chen JF, Sonsalla PK, Pedata F, et al (2007) Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and “fine tuning” modulation. Prog Neurobiol 83(5):310–331Google Scholar
  91. 91.
    Gomes CV, Kaster MP, Tome AR, Agostinho PM, Cunha RA (2011) Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. Biochim Biophys Acta 1808(5):1380–1399Google Scholar
  92. 92.
    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(5–6):331–348Google Scholar
  93. 93.
    Rivera-Oliver M, Diaz-Rios M (2014) Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review. Life Sci 101(1–2):1–9Google Scholar
  94. 94.
    Cunha-Santos J, Duarte-Neves J, Carmona V, Guarente L, Pereira de Almeida L, Cavadas C (2016) Caloric restriction blocks neuropathology and motor deficits in Machado-Joseph disease mouse models through SIRT1 pathway. Nat Commun 7:11445Google Scholar
  95. 95.
    Martin A, Tegla CA, Cudrici CD, et al (2015) Role of SIRT1 in autoimmune demyelination and neurodegeneration. Immunol Res 61(3):187–197Google Scholar
  96. 96.
    Jeong H, Cohen DE, Cui L, et al (2012) Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med 18(1):159–165Google Scholar
  97. 97.
    Jiang M, Wang J, Fu J, et al (2012) Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med 18(1):153–158Google Scholar
  98. 98.
    Montie HL, Pestell RG, Merry DE (2011) SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA. J Neurosci 31(48):17425–17436Google Scholar
  99. 99.
    Torashima T, Koyama C, Iizuka A, et al (2008) Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia. EMBO reports 9(4):393–399Google Scholar
  100. 100.
    Walle T (2011) Bioavailability of resveratrol. Ann NY Acad Sci 1215:9–15Google Scholar
  101. 101.
    Teixeira-Castro A, Jalles A, Esteves S, et al (2015) Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Brain: J Neurol 138(Pt 11):3221–3237Google Scholar
  102. 102.
    Tatum MC, Ooi FK, Chikka MR, et al (2015) Neuronal serotonin release triggers the heat shock response in C. elegans in the absence of temperature increase. Curr Biol 25(2):163–174Google Scholar
  103. 103.
    Koch P, Breuer P, Peitz M, et al (2011) Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480(7378):543–546Google Scholar
  104. 104.
    Konno A, Shuvaev AN, Miyake N, Miyake K, et al (2014) Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar Purkinje cells. Cerebellum 13(1):29–41Google Scholar
  105. 105.
    Ristori G, Romano S, Visconti A, et al (2010) Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology 74(10):839–845Google Scholar
  106. 106.
    Romano S, Coarelli G, Marcotulli C, et al (2015) Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 14(10):985–991Google Scholar
  107. 107.
    Hockly E, Tse J, Barker AL, et al (2006) Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington’s disease. Neurobiol Dis 21(1):228–236Google Scholar
  108. 108.
    Ortega Z, Diaz-Hernandez M, Maynard CJ, Hernandez F, Dantuma NP, Lucas JJ (2010) Acute polyglutamine expression in inducible mouse model unravels ubiquitin/proteasome system impairment and permanent recovery attributable to aggregate formation. J Neurosci 30(10):3675–3688Google Scholar
  109. 109.
    Boy J, Schmidt T, Wolburg H, et al (2009) Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3. Hum mol genet 18(22):4282–4295Google Scholar
  110. 110.
    Schmidt J, Schmidt T, Golla M, et al (2016) In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3. J Neurochem 138(1):150–162Google Scholar
  111. 111.
    Sakai T, Matsuishi T, Yamada S, Komori H, Iwashita H (1995) Sulfamethoxazole-trimethoprim double-blind, placebo-controlled, crossover trial in Machado-Joseph disease: sulfamethoxazole-trimethoprim increases cerebrospinal fluid level of biopterin. J Neural Transm Gen Sect 102(2):159–172Google Scholar
  112. 112.
    Correia M, Coutinho P, Silva MC, Guimaraes J, Amado J, Matos E (1995) Evaluation of the effect of sulphametoxazole and trimethoprim in patients with Machado-Joseph disease. Rev Neurol 23(121):632–634Google Scholar
  113. 113.
    Schulte T, Mattern R, Berger K, et al (2001) Double-blind crossover trial of trimethoprim-sulfamethoxazole in spinocerebellar ataxia type 3/Machado-Joseph disease. Arch Neurol 58(9):1451–1457Google Scholar
  114. 114.
    Chan-Palay V (1977) Indoleamine neurons and their processes in the normal rat brain and in chronic diet-induced thiamine deficiency demonstrated by uptake of 3H-serotonin. J Comp Neurol 176(4):467–493Google Scholar
  115. 115.
    Wenthur CJ, Bennett MR, Lindsley CW (2014) Classics in chemical neuroscience: fluoxetine (Prozac). ACS Chem Neurosci 5(1):14–23Google Scholar
  116. 116.
    Monte TL, Rieder CR, Tort AB, et al (2003) Use of fluoxetine for treatment of Machado-Joseph disease: an open-label study. Acta Neurol Scand 107(3):207–210Google Scholar
  117. 117.
    Lou JS, Goldfarb L, McShane L, Gatev P, Hallett M (1995) Use of buspirone for treatment of cerebellar ataxia. An open-label study. Arch Neurol 52(10):982–988Google Scholar
  118. 118.
    Trouillas P, Brudon F, Adeleine P (1988) Improvement of cerebellar ataxia with levorotatory form of 5-hydroxytryptophan. A double-blind study with quantified data processing. Arch Neurol 45(11):1217–1222Google Scholar
  119. 119.
    Trouillas P, Xie J, Adeleine P (1997) Buspirone, a serotonergic 5-HT1A agonist, is active in cerebellar ataxia. A new fact in favor of the serotonergic theory of ataxia. Prog Brain Res 114:589–599Google Scholar
  120. 120.
    Trouillas P, Xie J, Adeleine P, et al (1997) Buspirone, a 5-hydroxytryptamine1A agonist, is active in cerebellar ataxia. Results of a double-blind drug placebo study in patients with cerebellar cortical atrophy. Arch Neurol 54(6):749–752Google Scholar
  121. 121.
    Friedman JH (1997) Machado-Joseph disease/spinocerebellar ataxia 3 responsive to buspirone. Mov Disord: Official J Mov Disord Soc 12(4):613–614Google Scholar
  122. 122.
    Takei A, Honma S, Kawashima A, et al (2002) Beneficial effects of tandospirone on ataxia of a patient with Machado-Joseph disease. Psychiatry Clin Neurosci 56(2):181–185Google Scholar
  123. 123.
    Takei A, Fukazawa T, Hamada T, et al (2004) Effects of tandospirone on “5-HT1A receptor-associated symptoms” in patients with Machado-Josephe disease: an open-label study. Clin Neuropharmacol 27(1):9–13Google Scholar
  124. 124.
    Lanfumey L, Hamon M (2004) 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord 3(1):1–10Google Scholar
  125. 125.
    Blier P, Ward NM (2003) Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 53(3):193–203Google Scholar
  126. 126.
    Ientile R, Caccamo D, Macaione V, Torre V, Macaione S (2002) NMDA-evoked excitotoxicity increases tissue transglutaminase in cerebellar granule cells. Neuroscience 115(3):723–729Google Scholar
  127. 127.
    Liu CS, Hsu HM, Cheng WL, Hsieh M (2005) Clinical and molecular events in patients with Machado-Joseph disease under lamotrigine therapy. Acta Neurol Scand 111(6):385–390Google Scholar
  128. 128.
    Zesiewicz TA, Sullivan KL (2008) Treatment of ataxia and imbalance with varenicline (Chantix): report of 2 patients with spinocerebellar ataxia (types 3 and 14). Clin Neuropharmacol 31(6):363–365Google Scholar
  129. 129.
    Zesiewicz TA, Sullivan KL, Freeman A, Juncos JL (2009) Treatment of imbalance with varenicline Chantix®: report of a patient with fragile X tremor/ataxia syndrome. Acta Neurol Scand 119(2):135–138Google Scholar
  130. 130.
    Zesiewicz TA, Sullivan KL, Gooch CL, Lynch DR (2009) Subjective improvement in proprioception in 2 patients with atypical Friedreich ataxia treated with varenicline (Chantix). J Clin Neuromuscul Dis 10(4):191–193Google Scholar
  131. 131.
    Zesiewicz TA, Greenstein PE, Sullivan KL, Wecker L, Miller A, Jahan I, Chen R, Perlman SL (2012) A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 78(8):545–550Google Scholar
  132. 132.
    Goodwin FK (2003) Rationale for using lithium in combination with other mood stabilizers in the management of bipolar disorder. J Clin Psychiatry 64(Suppl 5):18–24Google Scholar
  133. 133.
    Lin D, Mok H, Yatham LN (2006) Polytherapy in bipolar disorder. CNS Drugs 20(1):29–42Google Scholar
  134. 134.
    Wood NI, Morton AJ (2003) Chronic lithium chloride treatment has variable effects on motor behaviour and survival of mice transgenic for the Huntington’s disease mutation. Brain res bull 61(4):375–383Google Scholar
  135. 135.
    Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM (2008) Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155(3):567–572Google Scholar
  136. 136.
    Jia DD, Zhang L, Chen Z, et al (2013) Lithium chloride alleviates neurodegeneration partly by inhibiting activity of GSK3beta in a SCA3 Drosophila model. Cerebellum 12(6):892–901Google Scholar
  137. 137.
    Fornai F, Longone P, Cafaro L, et al (2008) Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 105(6):2052–2057Google Scholar
  138. 138.
    Watase K, Gatchel JR, Sun Y, et al (2007) Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med 4(5):e182Google Scholar
  139. 139.
    van Gaalen J, Kerstens FG, Maas RP, Harmark L, van de Warrenburg BP (2014) Drug-induced cerebellar ataxia: a systematic review. CNS Drugs 28(12):1139–1153Google Scholar
  140. 140.
    Saute JA, Castilhos RM, Monte TL, et al (2014) A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease. Mov Disord: Official J Mov Disord SocGoogle Scholar
  141. 141.
    Yi J, Zhang L, Tang B, et al (2013) Sodium valproate alleviates neurodegeneration in SCA3/MJD via suppressing apoptosis and rescuing the hypoacetylation levels of histone H3 and H4. PLoS ONE 8(1):e54792Google Scholar
  142. 142.
    Lei LF, Yang GP, Wang JL, et al (2016) Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord 26:55–61Google Scholar
  143. 143.
    Saute JA, Donis KC, Serrano-Munuera C, et al (2012) Ataxia rating scales—psychometric profiles, natural history and their application in clinical trials. Cerebellum 11(2):488–504Google Scholar
  144. 144.
    Kieling C, Morales Saute JA, Jardim LB (2007) When ataxia is not just ataxia. Nat Clin Pract Neurol 3(5):E2Google Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Life and Health Sciences Research Institute (ICVS), School of MedicineUniversity of MinhoBragaPortugal
  2. 2.ICVS/3B’s—PT Government Associate LaboratoryBraga, GuimarãesPortugal

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