The Cerebellum

, Volume 9, Issue 2, pp 148–166 | Cite as

Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias

  • Antoni Matilla-DueñasEmail author
  • Ivelisse Sánchez
  • Marc Corral-Juan
  • Antoni Dávalos
  • Ramiro Alvarez
  • Pilar Latorre


The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. To date, more than 30 genes have been identified triggering the well-described clinical and pathological phenotype, but the underlying cellular and molecular events are still poorly understood. Studies of the functions of the proteins implicated in SCAs and the corresponding altered cellular pathways point to major aetiological roles for defects in transcriptional regulation, protein aggregation and clearance, alterations of calcium homeostasis, and activation of pro-apoptotic routes among others, all leading to synaptic neurotransmission deficits, spinocerebellar dysfunction, and, ultimately, neuronal demise. However, more mechanistic and detailed insights are emerging on these molecular routes. The growing understanding of how dysregulation of these pathways trigger the onset of symptoms and mediate disease progression is leading to the identification of conserved molecular targets influencing the critical pathways in pathogenesis that will serve as effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed cellular and molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the ongoing therapeutic strategies.


Spinocerebellar ataxias Cerebellum Neurodegenerative disorders Neurodegenerative mechanisms Therapy 



Autosomal dominant spinocerebellar ataxia


Calcium ion


Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit


DNA sequence coding for glutamine


Central nervous system


Dentatorubral-pallidoluysian atrophy


Endoplasmic reticulum


Fibroblast growth factor 14


γ-aminobutyric acid




Histone deacetylases


Heat shock protein


Inositol 1,4,5-triphosphate receptor type 1


Potassium voltage-gated channel subfamily C member 3


Machado–Joseph disease


Purkinje cells


Protein phosphatase 2 (formerly 2A)


Serine/threonine protein phosphatase 2 (formerly 2A) 55 kDa regulatory subunit B beta isoform


Protein kinase C gamma




Spinocerebellar ataxia


Beta-III spectrin


TATA-box-binding protein


Unfolded protein response


Ubiquitin-dependent proteasome system



Antoni Matilla-Dueñas' ataxia research is funded by the Spanish Ministry of Science and Innovation (BFU2008-00527/BMC), the Carlos III Health Institute (CP08/00027) and the European Commission (EUROSCA project, LHSM-CT-2004-503304). We are indebted to the Spanish Ataxia Association (FEDAES) and the ataxia patients for their continuous support and motivation. Antoni Matilla is a Miguel Servet Investigator in Neurosciences of the Spanish National Health System.


  1. 1.
    Matilla-Dueñas A, Goold R, Giunti P (2006) Molecular pathogenesis of spinocerebellar ataxias. Brain 129:1357–1370CrossRefGoogle Scholar
  2. 2.
    Tsuji S, Onodera O, Goto J, Nishizawa M (2008) Sporadic ataxias in Japan—a population-based epidemiological study. Cerebellum 7:189–197PubMedCrossRefGoogle Scholar
  3. 3.
    Schols L, Peters S, Szymanski S, Kruger R, Lange S, Hardt C et al (2000) Extrapyramidal motor signs in degenerative ataxias. Arch Neurol 57:1495–1500PubMedCrossRefGoogle Scholar
  4. 4.
    Riess O, Rub U, Pastore A, Bauer P, Schols L (2008) SCA3: neurological features, pathogenesis and animal models. Cerebellum 7:125–137PubMedCrossRefGoogle Scholar
  5. 5.
    Wang YG, Du J, Wang JL, Chen J, Chen C, Luo YY et al (2009) Six cases of SCA3/MJD patients that mimic hereditary spastic paraplegia in clinic. J Neurol Sci 285:121–124PubMedCrossRefGoogle Scholar
  6. 6.
    Gan SR, Zhao K, Wu ZY, Wang N, Murong SX (2009) Chinese patients with Machado-Joseph disease presenting with complicated hereditary spastic paraplegia. Eur J Neurol 16:953–956PubMedCrossRefGoogle Scholar
  7. 7.
    Lukas C, Hahn HK, Bellenberg B, Hellwig K, Globas C, Schimrigk SK et al (2008) Spinal cord atrophy in spinocerebellar ataxia type 3 and 6: impact on clinical disability. J Neurol 255:1244–1249PubMedCrossRefGoogle Scholar
  8. 8.
    Tan EK, Tong J, Pavanni R, Wong MC, Zhao Y (2007) Genetic analysis of SCA 2 and 3 repeat expansions in essential tremor and atypical Parkinsonism. Mov Disord 22:1971–1974PubMedCrossRefGoogle Scholar
  9. 9.
    Reimold M, Globas C, Gleichmann M, Schulze M, Gerloff C, Bares R et al (2006) Spinocerebellar ataxia type 1, 2, and 3 and restless legs syndrome: striatal dopamine D2 receptor status investigated by [11C]raclopride positron emission tomography. Mov Disord 21:1667–1673PubMedCrossRefGoogle Scholar
  10. 10.
    Friedman JH, Fernandez HH, Sudarsky LR (2003) REM behavior disorder and excessive daytime somnolence in Machado–Joseph disease (SCA-3). Mov Disord 18:1520–1522PubMedCrossRefGoogle Scholar
  11. 11.
    Pradhan C, Yashavantha BS, Pal PK, Sathyaprabha TN (2008) Spinocerebellar ataxias type 1, 2 and 3: a study of heart rate variability. Acta Neurol Scand 117:337–342PubMedCrossRefGoogle Scholar
  12. 12.
    van de Warrenburg BP, Notermans NC, Schelhaas HJ, van Alfen N, Sinke RJ, Knoers NV et al (2004) Peripheral nerve involvement in spinocerebellar ataxias. Arch Neurol 61:257–261PubMedCrossRefGoogle Scholar
  13. 13.
    Burk K, Globas C, Bosch S, Klockgether T, Zuhlke C, Daum I et al (2003) Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. J Neurol 250:207–211PubMedCrossRefGoogle Scholar
  14. 14.
    Gupta SN, Marks HG (2008) Spinocerebellar ataxia type 7 mimicking Kearns–Sayre syndrome: a clinical diagnosis is desirable. J Neurol Sci 264:173–176PubMedCrossRefGoogle Scholar
  15. 15.
    Wardle M, Morris HR, Robertson NP (2009) Clinical and genetic characteristics of non-Asian dentatorubral-pallidoluysian atrophy: a systematic review. Mov Disord 24:1636–1640PubMedCrossRefGoogle Scholar
  16. 16.
    Matilla-Dueñas A (2008) The highly heterogeneous spinocerebellar ataxias: from genes to targets for therapeutic intervention. Cerebellum 7:97–100PubMedCrossRefGoogle Scholar
  17. 17.
    Holmes SE, O'Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C et al (1999) Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nat Genet 23:391–392PubMedCrossRefGoogle Scholar
  18. 18.
    Wakamiya M, Matsuura T, Liu Y, Schuster GC, Gao R, Xu W et al (2006) The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10. Neurology 67:607–613PubMedCrossRefGoogle Scholar
  19. 19.
    Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ et al (2009) RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet 5:e1000600PubMedCrossRefGoogle Scholar
  20. 20.
    Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC et al (2006) Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 38:184–190PubMedCrossRefGoogle Scholar
  21. 21.
    Houlden H, Johnson J, Gardner-Thorpe C, Lashley T, Hernandez D, Worth P et al (2007) Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet 39:1434–1436PubMedCrossRefGoogle Scholar
  22. 22.
    Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JP, Nolte D et al (2006) Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet 38:447–451PubMedCrossRefGoogle Scholar
  23. 23.
    Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D et al (2003) Missense mutations in the regulatory domain of PKCgamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet 72:839–849PubMedCrossRefGoogle Scholar
  24. 24.
    Yabe I, Sasaki H, Chen DH, Raskind WH, Bird TD, Yamashita I et al (2003) Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma. Arch Neurol 60:1749–1751PubMedCrossRefGoogle Scholar
  25. 25.
    van de Leemput J, Chandran J, Knight MA, Holtzclaw LA, Scholz S, Cookson MR et al (2007) Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet 3:e108PubMedCrossRefGoogle Scholar
  26. 26.
    van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I et al (2003) A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebral ataxia. Am J Hum Genet 72:191–199PubMedCrossRefGoogle Scholar
  27. 27.
    Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G (2009) Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration. J Neurosci 29:9244–9254PubMedCrossRefGoogle Scholar
  28. 28.
    Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23:217–247PubMedCrossRefGoogle Scholar
  29. 29.
    Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:S10–S17PubMedCrossRefGoogle Scholar
  30. 30.
    Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19:148–154PubMedCrossRefGoogle Scholar
  31. 31.
    McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J et al (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9:2197–2202PubMedCrossRefGoogle Scholar
  32. 32.
    Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J et al (2002) Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol 51:302–310PubMedCrossRefGoogle Scholar
  33. 33.
    Chai Y, Berke SS, Cohen RE, Paulson HL (2004) Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J Biol Chem 279:3605–3611PubMedCrossRefGoogle Scholar
  34. 34.
    Park Y, Hong S, Kim SJ, Kang S (2005) Proteasome function is inhibited by polyglutamine-expanded ataxin-1, the SCA1 gene product. Mol Cells 19:23–30PubMedGoogle Scholar
  35. 35.
    Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, De Camilli P (2005) Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc Natl Acad Sci USA 102:12700–12705PubMedCrossRefGoogle Scholar
  36. 36.
    Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM (2004) Caspase activation inhibits proteasome function during apoptosis. Mol Cell 14:81–93PubMedCrossRefGoogle Scholar
  37. 37.
    Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT et al (2001) Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet 10:1511–1518PubMedCrossRefGoogle Scholar
  38. 38.
    Bonini NM (2002) Chaperoning brain degeneration. Proc Nat Acad Sci USA 99:16407–16411PubMedCrossRefGoogle Scholar
  39. 39.
    Sakahira H, Breuer P, Hayer-Hartl MK, Hartl FU (2002) Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Nat Acad Sci USA 99:16412–16418PubMedCrossRefGoogle Scholar
  40. 40.
    He C, Klionsky DJ (2009) Regulation Mechanisms and Signaling Pathways of Autophagy. Annu Rev Genet (in press)Google Scholar
  41. 41.
    Iwata A, Christianson JC, Bucci M, Ellerby LM, Nukina N, Forno LS et al (2005) Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation. Proc Nat Acad Sci USA 102:13135–13140PubMedCrossRefGoogle Scholar
  42. 42.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595PubMedCrossRefGoogle Scholar
  43. 43.
    Helmlinger D, Tora L, Devys D (2006) Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet 22:562–570PubMedCrossRefGoogle Scholar
  44. 44.
    Matilla A, Koshy BT, Cummings CJ, Isobe T, Orr HT, Zoghbi HY (1997) The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature 389:974–978PubMedCrossRefGoogle Scholar
  45. 45.
    Okazawa H, Rich T, Chang A, Lin X, Waragai M, Kajikawa M et al (2002) Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron 34:701–713PubMedCrossRefGoogle Scholar
  46. 46.
    Tsai CC, Kao HY, Mitzutani A, Banayo E, Rajan H, McKeown M et al (2004) Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proc Nat Acad Sci USA 101:4047–4052PubMedCrossRefGoogle Scholar
  47. 47.
    Mizutani A, Wang L, Rajan H, Vig PJ, Alaynick WA, Thaler JP et al (2005) Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J 24:3339–3351PubMedCrossRefGoogle Scholar
  48. 48.
    Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF et al (2005) The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/senseless proteins. Cell 122:633–644PubMedCrossRefGoogle Scholar
  49. 49.
    Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD et al (2006) ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127:1335–1347PubMedCrossRefGoogle Scholar
  50. 50.
    Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N et al (2006) RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 127:697–708PubMedCrossRefGoogle Scholar
  51. 51.
    Goold R, Hubank M, Hunt A, Holton J, Menon RP, Revesz T et al (2007) Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1. Hum Mol Genet 16:2122–2134PubMedCrossRefGoogle Scholar
  52. 52.
    Matilla-Dueñas A, Goold R, Giunti P (2008) Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. Cerebellum 7:106–114PubMedCrossRefGoogle Scholar
  53. 53.
    Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, Naruse S et al (2000) Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26:29–36PubMedCrossRefGoogle Scholar
  54. 54.
    Li F, Macfarlan T, Pittman RN, Chakravarti D (2002) Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem 277:45004–45012PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang S, Xu L, Lee J, Xu T (2002) Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell 108:45–56PubMedCrossRefGoogle Scholar
  56. 56.
    Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C et al (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 13:1257–1265PubMedCrossRefGoogle Scholar
  57. 57.
    Friedman MJ, Shah AG, Fang ZH, Ward EG, Warren ST, Li S et al (2007) Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration. Nat Neurosci 10:1519–1528PubMedCrossRefGoogle Scholar
  58. 58.
    Matilla A, Radrizzani M (2005) The Anp32 family of proteins containing leucine-rich repeats. Cerebellum 4:7–18PubMedCrossRefGoogle Scholar
  59. 59.
    La Spada AR, Fu Y, Sopher BL, Libby RT, Wang X, Li LY et al (2001) Polyglutamine-expanded ataxin-7 antagonizes crx function and induces cone-rod dystrophy in a mouse model of sca7. Neuron 31:913–927PubMedCrossRefGoogle Scholar
  60. 60.
    Kouzarides T (2000) Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19:1176–1179PubMedCrossRefGoogle Scholar
  61. 61.
    Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL et al (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743PubMedCrossRefGoogle Scholar
  62. 62.
    McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS, Fischbeck KH (2001) Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Nat Acad Sci USA 98:15179–15184PubMedCrossRefGoogle Scholar
  63. 63.
    Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E et al (2003) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Nat Acad Sci USA 100:2041–2046PubMedCrossRefGoogle Scholar
  64. 64.
    Clark HB, Burright EN, Yunis WS, Larson S, Wilcox C, Hartman B et al (1997) Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations. J Neurosci 17:7385–7395PubMedGoogle Scholar
  65. 65.
    Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT (2004) Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet 13:2535–2543PubMedCrossRefGoogle Scholar
  66. 66.
    Ichise T, Kano M, Hashimoto K, Yanagihara D, Nakao K, Shigemoto R et al (2000) mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288:1832–1835PubMedCrossRefGoogle Scholar
  67. 67.
    Ikeda Y, Daughters RS, Ranum LP (2008) Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes. Cerebellum 7:150–158PubMedCrossRefGoogle Scholar
  68. 68.
    Worth PF, Houlden H, Giunti P, Davis MB, Wood NW (2000) Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. Nat Genet 24:214–215PubMedCrossRefGoogle Scholar
  69. 69.
    Corral J, Genis D, Banchs I, San Nicolas H, Armstrong J, Volpini V (2005) Giant SCA8 alleles in nine children whose mother has two moderately large ones. Ann Neurol 57:549–553PubMedCrossRefGoogle Scholar
  70. 70.
    Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY (2000) Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 3:157–163PubMedCrossRefGoogle Scholar
  71. 71.
    Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP et al (2009) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci 29:9148–9162PubMedCrossRefGoogle Scholar
  72. 72.
    Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C et al (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:62–69PubMedCrossRefGoogle Scholar
  73. 73.
    Pietrobon D (2002) Calcium channels and channelopathies of the central nervous system. Mol Neurobiol 25:31–50PubMedCrossRefGoogle Scholar
  74. 74.
    Saegusa H, Wakamori M, Matsuda Y, Wang J, Mori Y, Zong S et al (2007) Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Mol Cell Neurosci 34:261–270PubMedCrossRefGoogle Scholar
  75. 75.
    Adachi N, Kobayashi T, Takahashi H, Kawasaki T, Shirai Y, Ueyama T et al (2008) Enzymological analysis of mutant protein kinase Cgamma causing spinocerebellar ataxia type 14 and dysfunction in Ca2+ homeostasis. J Biol Chem 283:19854–19863PubMedCrossRefGoogle Scholar
  76. 76.
    Lipinski MM, Yuan J (2004) Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharm 4:85–90CrossRefGoogle Scholar
  77. 77.
    Sanchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, Yuan J (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22:623–633PubMedCrossRefGoogle Scholar
  78. 78.
    Chou AH, Yeh TH, Kuo YL, Kao YC, Jou MJ, Hsu CY et al (2006) Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-x(L). Neurobiol Dis 21:333–345PubMedCrossRefGoogle Scholar
  79. 79.
    Wang HL, Yeh TH, Chou AH, Kuo YL, Luo LJ, He CY et al (2006) Polyglutamine-expanded ataxin-7 activates mitochondrial apoptotic pathway of cerebellar neurons by upregulating Bax and downregulating Bcl-x(L). Cell Signal 18:541–552PubMedCrossRefGoogle Scholar
  80. 80.
    Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH et al (2003) Interaction of Akt-phosphorylated ataxin-1 with 14–3–3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457–468PubMedCrossRefGoogle Scholar
  81. 81.
    van de Warrenburg BP, Hendriks H, Durr A, van Zuijlen MC, Stevanin G, Camuzat A et al (2005) Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch–French cohort. Ann Neurol 57:505–512PubMedCrossRefGoogle Scholar
  82. 82.
    Albrecht M, Golatta M, Wullner U, Lengauer T (2004) Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem 271:3155–3170PubMedCrossRefGoogle Scholar
  83. 83.
    He W, Parker R (2000) Functions of Lsm proteins in mRNA degradation and splicing. Curr Opin Cell Biol 12:346–350PubMedCrossRefGoogle Scholar
  84. 84.
    Shibata H, Huynh DP, Pulst SM (2000) A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet 9:1303–1313PubMedCrossRefGoogle Scholar
  85. 85.
    Jin Y, Suzuki H, Maegawa S, Endo H, Sugano S, Hashimoto K et al (2003) A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG. EMBO J 22:905–912PubMedCrossRefGoogle Scholar
  86. 86.
    Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K et al (2000) Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 26:191–194PubMedCrossRefGoogle Scholar
  87. 87.
    Lin X, Ashizawa T (2005) Recent progress in spinocerebellar ataxia type-10 (SCA10). Cerebellum 4:37–42PubMedCrossRefGoogle Scholar
  88. 88.
    Coates JC (2003) Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol 13:463–471PubMedCrossRefGoogle Scholar
  89. 89.
    Sontag E (2001) Protein phosphatase 2A: the Trojan horse of cellular signaling. Cell Signal 13:7–16PubMedCrossRefGoogle Scholar
  90. 90.
    Lim J, Lu KP (2005) Pinning down phosphorylated tau and tauopathies. Biochim Biophys Acta 1739:311–322PubMedGoogle Scholar
  91. 91.
    Waters MF, Pulst SM (2008) Sca13. Cerebellum 7:165–169PubMedCrossRefGoogle Scholar
  92. 92.
    Newton AC (2001) Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101:2353–2364PubMedCrossRefGoogle Scholar
  93. 93.
    Schrenk K, Kapfhammer JP, Metzger F (2002) Altered dendritic development of cerebellar Purkinje cells in slice cultures from protein kinase Cgamma-deficient mice. Neuroscience 110:675–689PubMedCrossRefGoogle Scholar
  94. 94.
    Abeliovich A, Paylor R, Chen C, Kim JJ, Wehner JM, Tonegawa S (1993) PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. Cell 75:1263–1271PubMedCrossRefGoogle Scholar
  95. 95.
    Verbeek DS, Goedhart J, Bruinsma L, Sinke RJ, Reits EA (2008) PKC gamma mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling. J Cell Sci 121:2339–2349PubMedCrossRefGoogle Scholar
  96. 96.
    Wang Q, Bardgett ME, Wong M, Wozniak DF, Lou J, McNeil BD et al (2002) Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 35:25–38PubMedCrossRefGoogle Scholar
  97. 97.
    Shakkottai VG, Xiao M, Xu L, Wong M, Nerbonne JM, Ornitz DM et al (2009) FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiol Dis 33:81–88PubMedCrossRefGoogle Scholar
  98. 98.
    Ishikawa K, Toru S, Tsunemi T, Li M, Kobayashi K, Yokota T et al (2005) An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5′ untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains. Am J Hum Genet 77:280–296PubMedCrossRefGoogle Scholar
  99. 99.
    Flanigan K, Gardner K, Alderson K, Galster B, Otterud B, Leppert MF et al (1996) Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1. Am J Hum Genet 59:392–399PubMedGoogle Scholar
  100. 100.
    Manto M, Marmolino D (2009) Cerebellar ataxias. Curr Opin Neurol 22:419–429PubMedCrossRefGoogle Scholar
  101. 101.
    Trujillo-Martin MM, Serrano-Aguilar P, Monton-Alvarez F, Carrillo-Fumero R (2009) Effectiveness and safety of treatments for degenerative ataxias: a systematic review. Mov Disord 24:1111–1124PubMedCrossRefGoogle Scholar
  102. 102.
    Watase K, Gatchel JR, Sun Y, Emamian E, Atkinson R, Richman R et al (2007) Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med 4:e182PubMedCrossRefGoogle Scholar
  103. 103.
    Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT et al (2004) RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 10:816–820PubMedCrossRefGoogle Scholar
  104. 104.
    Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22PubMedCrossRefGoogle Scholar
  105. 105.
    Chan HY, Warrick JM, Gray-Board GL, Paulson HL, Bonini NM (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9:2811–2820PubMedCrossRefGoogle Scholar
  106. 106.
    Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R, Schugardt N et al (2000) Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. Proc Nat Acad Sci USA 97:6739–6744PubMedCrossRefGoogle Scholar
  107. 107.
    Sanchez I, Mahlke C, Yuan J (2003) Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421:373–379PubMedCrossRefGoogle Scholar
  108. 108.
    Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I (2002) Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Neurobiol Dis 10:88–99PubMedCrossRefGoogle Scholar
  109. 109.
    Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H et al (2004) Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10:148–154PubMedCrossRefGoogle Scholar
  110. 110.
    Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S et al (2002) Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc Nat Acad Sci USA 99:16400–16406PubMedCrossRefGoogle Scholar
  111. 111.
    Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE, Roark M et al (2005) A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Nat Acad Sci USA 102:892–897PubMedCrossRefGoogle Scholar
  112. 112.
    Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L (2004) Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 10:402–405PubMedCrossRefGoogle Scholar
  113. 113.
    Rimoldi M, Servadio A, Zimarino V (2001) Analysis of heat shock transcription factor for suppression of polyglutamine toxicity. Brain Res Bull 56:353–362PubMedCrossRefGoogle Scholar
  114. 114.
    Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918PubMedCrossRefGoogle Scholar
  115. 115.
    Dedeoglu A, Kubilus JK, Jeitner TM, Matson SA, Bogdanov M, Kowall NW et al (2002) Therapeutic effects of cystamine in a murine model of Huntington's disease. J Neurosci 22:8942–8950PubMedGoogle Scholar
  116. 116.
    Karpuj MV, Becher MW, Springer JE, Chabas D, Youssef S, Pedotti R et al (2002) Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med 8:143–149PubMedCrossRefGoogle Scholar
  117. 117.
    Shults CW (2003) Coenzyme Q10 in neurodegenerative diseases. Curr Med Chem 10:1917–1921PubMedCrossRefGoogle Scholar
  118. 118.
    Ryu H, Rosas HD, Hersch SM, Ferrante RJ (2005) The therapeutic role of creatine in Huntington's disease. Pharmacol Ther 108:193–207PubMedCrossRefGoogle Scholar
  119. 119.
    Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC (2002) Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Nat Acad Sci USA 99:10671–10676PubMedCrossRefGoogle Scholar
  120. 120.
    Ona VO, Li M, Vonsattel JP, Andrews LJ, Khan SQ, Chung WM et al (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399:263–267PubMedCrossRefGoogle Scholar
  121. 121.
    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S et al (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6:797–801PubMedCrossRefGoogle Scholar
  122. 122.
    Lesort M, Lee M, Tucholski J, Johnson GV (2003) Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J Biol Chem 278:3825–3830PubMedCrossRefGoogle Scholar
  123. 123.
    Gauthier S (2009) Dimebon improves cognitive function in people with mild to moderate Alzheimer's disease. Evid Based Ment Health 12:21PubMedCrossRefGoogle Scholar
  124. 124.
    Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C (2009) Therapeutic interventions for disease progression in Huntington's disease. Cochrane Database Syst Rev CD006455Google Scholar
  125. 125.
    Bordet T, Buisson B, Michaud M, Drouot C, Galea P, Delaage P et al (2007) Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther 322:709–720PubMedCrossRefGoogle Scholar
  126. 126.
    Strupp M, Kalla R, Glasauer S, Wagner J, Hufner K, Jahn K et al (2008) Aminopyridines for the treatment of cerebellar and ocular motor disorders. Prog Brain Res 171:535–541PubMedCrossRefGoogle Scholar
  127. 127.
    Dokmanovic M, Marks PA (2005) Prospects: Histone deacetylase inhibitors. J Cell Biochem 96:293–304PubMedCrossRefGoogle Scholar
  128. 128.
    Thomas EA, Coppola G, Desplats PA, Tang B, Soragni E, Burnett R et al (2008) The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice. Proc Natl Acad Sci USA 105:15564–15569PubMedCrossRefGoogle Scholar
  129. 129.
    Naoi M, Maruyama W, Yi H, Inaba K, Akao Y, Shamoto-Nagai M (2009) Mitochondria in neurodegenerative disorders: regulation of the redox state and death signaling leading to neuronal death and survival. J Neural Transm (in press)Google Scholar
  130. 130.
    Gatchel JR, Watase K, Thaller C, Carson JP, Jafar-Nejad P, Shaw C et al (2008) The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7. Proc Nat Acad Sci USA 105:1291–1296PubMedCrossRefGoogle Scholar
  131. 131.
    Fernandez AM, Carro EM, Lopez-Lopez C, Torres-Aleman I (2005) Insulin-like growth factor I treatment for cerebellar ataxia: Addressing a common pathway in the pathological cascade? Brain Res Rev 50:134–141PubMedCrossRefGoogle Scholar
  132. 132.
    Leinninger GM, Feldman EL (2005) Insulin-like growth factors in the treatment of neurological disease. Endocr Devel 9:135–159CrossRefGoogle Scholar
  133. 133.
    Gage FH (2002) Neurogenesis in the adult brain. J Neurosci 22:612–613PubMedGoogle Scholar
  134. 134.
    Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C et al (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720PubMedCrossRefGoogle Scholar
  135. 135.
    Schmitz-Hubsch T, Giunti P, Stephenson DA, Globas C, Baliko L, Sacca F et al (2008) SCA Functional Index: a useful compound performance measure for spinocerebellar ataxia. Neurology 71:486–492PubMedCrossRefGoogle Scholar
  136. 136.
    Lastres-Becker I, Rub U, Auburger G (2008) Spinocerebellar ataxia 2 (SCA2). Cerebellum 7:115–124PubMedCrossRefGoogle Scholar
  137. 137.
    Garden GA, La Spada AR (2008) Molecular pathogenesis and cellular pathology of spinocerebellar ataxia type 7 neurodegeneration. Cerebellum 7:138–149PubMedCrossRefGoogle Scholar
  138. 138.
    Higgins JJ, Pho LT, Ide SE, Nee LE, Polymeropoulos MH (1997) Evidence for a new spinocerebellar ataxia locus. Mov Disord 12:412–417PubMedCrossRefGoogle Scholar
  139. 139.
    Johnson J, Wood N, Giunti P, Houlden H (2008) Clinical and genetic analysis of spinocerebellar ataxia type 11. Cerebellum 7:159–164PubMedCrossRefGoogle Scholar
  140. 140.
    Miyoshi Y, Yamada T, Tanimura M, Taniwaki T, Arakawa K, Ohyagi Y et al (2001) A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1-24.1. Neurology 57:96–100PubMedGoogle Scholar
  141. 141.
    Stevanin G, Brice A (2008) Spinocerebellar ataxia 17 (SCA17) and Huntington's disease-like 4 (HDL4). Cerebellum 7:170–178PubMedCrossRefGoogle Scholar
  142. 142.
    Devos D, Schraen-Maschke S, Vuillaume I, Dujardin K, Naze P, Willoteaux C et al (2001) Clinical features and genetic analysis of a new form of spinocerebellar ataxia. Neurology 56:234–238PubMedGoogle Scholar
  143. 143.
    Verbeek DS, Schelhaas JH, Ippel EF, Beemer FA, Pearson PL, Sinke RJ (2002) Identification of a novel SCA locus (SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21–q21. Hum Genet 111:388–393PubMedCrossRefGoogle Scholar
  144. 144.
    Schelhaas HJ, van de Warrenburg BP (2005) Clinical, psychological, and genetic characteristics of spinocerebellar ataxia type 19 (SCA19). Cerebellum 4:51–54PubMedCrossRefGoogle Scholar
  145. 145.
    Knight MA, Hernandez D, Diede SJ, Dauwerse HG, Rafferty I, van de Leemput J et al (2008) A duplication at chromosome 11q12.2–11q12.3 is associated with spinocerebellar ataxia type 20. Hum Mol Genet 17:3847–3853PubMedCrossRefGoogle Scholar
  146. 146.
    Delplanque J, Devos D, Vuillaume I, De Becdelievre A, Vangelder E, Maurage CA et al (2008) Slowly progressive spinocerebellar ataxia with extrapyramidal signs and mild cognitive impairment (SCA21). Cerebellum 7:179–183PubMedCrossRefGoogle Scholar
  147. 147.
    Chung MY, Lu YC, Cheng NC, Soong BW (2003) A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21–q23. Brain 126:1293–1299PubMedCrossRefGoogle Scholar
  148. 148.
    Verbeek DS (2009) Spinocerebellar ataxia type 23: a genetic update. Cerebellum 8:104–107PubMedCrossRefGoogle Scholar
  149. 149.
    Stevanin G, Broussolle E, Streichenberger N, Kopp N, Brice A, Durr A (2005) Spinocerebellar ataxia with sensory neuropathy (SCA25). Cerebellum 4:58–61PubMedCrossRefGoogle Scholar
  150. 150.
    Yu GY, Howell MJ, Roller MJ, Xie TD, Gomez CM (2005) Spinocerebellar ataxia type 26 maps to chromosome 19p13.3 adjacent to SCA6. Ann Neurol 57:349–354PubMedCrossRefGoogle Scholar
  151. 151.
    Mariotti C, Brusco A, Di Bella D, Cagnoli C, Seri M, Gellera C et al (2008) Spinocerebellar ataxia type 28: a novel autosomal dominant cerebellar ataxia characterized by slow progression and ophthalmoparesis. Cerebellum 7:184–188PubMedCrossRefGoogle Scholar
  152. 152.
    Dudding TE, Friend K, Schofield PW, Lee S, Wilkinson IA, Richards RI (2004) Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology 63:2288–2292PubMedGoogle Scholar
  153. 153.
    Storey E, Bahlo M, Fahey M, Sisson O, Lueck CJ, Gardner RJ (2009) A new dominantly inherited pure cerebellar ataxia, SCA 30. J Neurol Neurosurg Psychiatry 80:408–411PubMedCrossRefGoogle Scholar
  154. 154.
    Tsuji S (2002) Dentatorubral-pallidoluysian atrophy: clinical aspects and molecular genetics. Adv Neurol 89:231–239PubMedGoogle Scholar
  155. 155.
    Genis D, Ferrer I, Sole JV, Corral J, Volpini V, San Nicolas H et al (2009) A kindred with cerebellar ataxia and thermoanalgesia. J Neurol Neurosurg Psychiatry 80:518–523PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Antoni Matilla-Dueñas
    • 1
    • 2
    Email author
  • Ivelisse Sánchez
    • 1
  • Marc Corral-Juan
    • 1
  • Antoni Dávalos
    • 1
  • Ramiro Alvarez
    • 1
  • Pilar Latorre
    • 1
  1. 1.Department of Neurosciences and Neurology Service, Health Sciences Research Institute and Hospital Germans Trias i PujolUniversitat Autònoma de BarcelonaBadalonaSpain
  2. 2.Basic, Translational and Neurogenetics Research Unit, Health Sciences Research Institute Germans Trias i Pujol (IGTP)Universitat Autònoma de BarcelonaBadalonaSpain

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