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Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias

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Abstract

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.

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Abbreviations

ADCA:

Autosomal dominant spinocerebellar ataxia

Ca2+ :

Calcium ion

CACNA1A:

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

CAG:

DNA sequence coding for glutamine

CNS:

Central nervous system

DRPLA:

Dentatorubral-pallidoluysian atrophy

ER:

Endoplasmic reticulum

FGF14:

Fibroblast growth factor 14

GABA:

γ-aminobutyric acid

Glu:

Glutamate

HDACs:

Histone deacetylases

HSP:

Heat shock protein

ITPR1:

Inositol 1,4,5-triphosphate receptor type 1

KCNC3:

Potassium voltage-gated channel subfamily C member 3

MJD:

Machado–Joseph disease

PC:

Purkinje cells

PP2:

Protein phosphatase 2 (formerly 2A)

PPP2R2B:

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

PRKCG:

Protein kinase C gamma

Q:

Glutamine

SCA:

Spinocerebellar ataxia

SPTBN2:

Beta-III spectrin

TBP:

TATA-box-binding protein

UPR:

Unfolded protein response

UPS:

Ubiquitin-dependent proteasome system

References

  1. Matilla-Dueñas A, Goold R, Giunti P (2006) Molecular pathogenesis of spinocerebellar ataxias. Brain 129:1357–1370

    Article  Google Scholar 

  2. Tsuji S, Onodera O, Goto J, Nishizawa M (2008) Sporadic ataxias in Japan—a population-based epidemiological study. Cerebellum 7:189–197

    Article  CAS  PubMed  Google Scholar 

  3. Schols L, Peters S, Szymanski S, Kruger R, Lange S, Hardt C et al (2000) Extrapyramidal motor signs in degenerative ataxias. Arch Neurol 57:1495–1500

    Article  CAS  PubMed  Google Scholar 

  4. Riess O, Rub U, Pastore A, Bauer P, Schols L (2008) SCA3: neurological features, pathogenesis and animal models. Cerebellum 7:125–137

    Article  CAS  PubMed  Google Scholar 

  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 285:121–124

    Article  PubMed  Google Scholar 

  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 16:953–956

    Article  PubMed  Google Scholar 

  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 255:1244–1249

    Article  PubMed  Google Scholar 

  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 22:1971–1974

    Article  PubMed  Google Scholar 

  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 21:1667–1673

    Article  PubMed  Google Scholar 

  10. Friedman JH, Fernandez HH, Sudarsky LR (2003) REM behavior disorder and excessive daytime somnolence in Machado–Joseph disease (SCA-3). Mov Disord 18:1520–1522

    Article  PubMed  Google Scholar 

  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 117:337–342

    Article  CAS  PubMed  Google Scholar 

  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 61:257–261

    Article  PubMed  Google Scholar 

  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 250:207–211

    Article  CAS  PubMed  Google Scholar 

  14. Gupta SN, Marks HG (2008) Spinocerebellar ataxia type 7 mimicking Kearns–Sayre syndrome: a clinical diagnosis is desirable. J Neurol Sci 264:173–176

    Article  PubMed  Google Scholar 

  15. Wardle M, Morris HR, Robertson NP (2009) Clinical and genetic characteristics of non-Asian dentatorubral-pallidoluysian atrophy: a systematic review. Mov Disord 24:1636–1640

    Article  PubMed  Google Scholar 

  16. Matilla-Dueñas A (2008) The highly heterogeneous spinocerebellar ataxias: from genes to targets for therapeutic intervention. Cerebellum 7:97–100

    Article  PubMed  CAS  Google Scholar 

  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 23:391–392

    Article  CAS  PubMed  Google Scholar 

  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 67:607–613

    Article  CAS  PubMed  Google Scholar 

  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:e1000600

    Article  PubMed  CAS  Google Scholar 

  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 38:184–190

    Article  CAS  PubMed  Google Scholar 

  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 39:1434–1436

    Article  CAS  PubMed  Google Scholar 

  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 38:447–451

    Article  CAS  PubMed  Google Scholar 

  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 72:839–849

    Article  CAS  PubMed  Google Scholar 

  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 60:1749–1751

    Article  PubMed  Google Scholar 

  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:e108

    Article  PubMed  CAS  Google Scholar 

  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 72:191–199

    Article  PubMed  Google Scholar 

  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 29:9244–9254

    Article  CAS  PubMed  Google Scholar 

  28. Zoghbi HY, Orr HT (2000) Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23:217–247

    Article  CAS  PubMed  Google Scholar 

  29. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:S10–S17

    Article  PubMed  CAS  Google Scholar 

  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 19:148–154

    Article  CAS  PubMed  Google Scholar 

  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 9:2197–2202

    Article  CAS  PubMed  Google Scholar 

  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 51:302–310

    Article  CAS  PubMed  Google Scholar 

  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 279:3605–3611

    Article  CAS  PubMed  Google Scholar 

  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 19:23–30

    CAS  PubMed  Google Scholar 

  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 102:12700–12705

    Article  CAS  PubMed  Google Scholar 

  36. Sun XM, Butterworth M, MacFarlane M, Dubiel W, Ciechanover A, Cohen GM (2004) Caspase activation inhibits proteasome function during apoptosis. Mol Cell 14:81–93

    Article  CAS  PubMed  Google Scholar 

  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 10:1511–1518

    Article  CAS  PubMed  Google Scholar 

  38. Bonini NM (2002) Chaperoning brain degeneration. Proc Nat Acad Sci USA 99:16407–16411

    Article  CAS  PubMed  Google Scholar 

  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 99:16412–16418

    Article  CAS  PubMed  Google Scholar 

  40. He C, Klionsky DJ (2009) Regulation Mechanisms and Signaling Pathways of Autophagy. Annu Rev Genet (in press)

  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 102:13135–13140

    Article  CAS  PubMed  Google Scholar 

  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 36:585–595

    Article  CAS  PubMed  Google Scholar 

  43. Helmlinger D, Tora L, Devys D (2006) Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet 22:562–570

    Article  CAS  PubMed  Google Scholar 

  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 389:974–978

    Article  CAS  PubMed  Google Scholar 

  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 34:701–713

    Article  CAS  PubMed  Google Scholar 

  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 101:4047–4052

    Article  CAS  PubMed  Google Scholar 

  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 24:3339–3351

    Article  CAS  PubMed  Google Scholar 

  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 122:633–644

    Article  CAS  PubMed  Google Scholar 

  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 127:1335–1347

    Article  CAS  PubMed  Google Scholar 

  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 127:697–708

    Article  CAS  PubMed  Google Scholar 

  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 16:2122–2134

    Article  CAS  PubMed  Google Scholar 

  52. Matilla-Dueñas A, Goold R, Giunti P (2008) Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. Cerebellum 7:106–114

    Article  PubMed  CAS  Google Scholar 

  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 26:29–36

    Article  CAS  PubMed  Google Scholar 

  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 277:45004–45012

    Article  CAS  PubMed  Google Scholar 

  55. Zhang S, Xu L, Lee J, Xu T (2002) Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell 108:45–56

    Article  CAS  PubMed  Google Scholar 

  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 13:1257–1265

    Article  CAS  PubMed  Google Scholar 

  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 10:1519–1528

    Article  CAS  PubMed  Google Scholar 

  58. Matilla A, Radrizzani M (2005) The Anp32 family of proteins containing leucine-rich repeats. Cerebellum 4:7–18

    Article  CAS  PubMed  Google Scholar 

  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 31:913–927

    Article  PubMed  Google Scholar 

  60. Kouzarides T (2000) Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19:1176–1179

    Article  CAS  PubMed  Google Scholar 

  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 413:739–743

    Article  CAS  PubMed  Google Scholar 

  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 98:15179–15184

    Article  CAS  PubMed  Google Scholar 

  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 100:2041–2046

    Article  CAS  PubMed  Google Scholar 

  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 17:7385–7395

    CAS  PubMed  Google Scholar 

  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 13:2535–2543

    Article  CAS  PubMed  Google Scholar 

  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 288:1832–1835

    Article  CAS  PubMed  Google Scholar 

  67. Ikeda Y, Daughters RS, Ranum LP (2008) Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes. Cerebellum 7:150–158

    Article  CAS  PubMed  Google Scholar 

  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 24:214–215

    Article  CAS  PubMed  Google Scholar 

  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 57:549–553

    Article  CAS  PubMed  Google Scholar 

  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 3:157–163

    Article  CAS  PubMed  Google Scholar 

  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 29:9148–9162

    Article  CAS  PubMed  Google Scholar 

  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 15:62–69

    Article  CAS  PubMed  Google Scholar 

  73. Pietrobon D (2002) Calcium channels and channelopathies of the central nervous system. Mol Neurobiol 25:31–50

    Article  CAS  PubMed  Google Scholar 

  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 34:261–270

    Article  CAS  PubMed  Google Scholar 

  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 283:19854–19863

    Article  CAS  PubMed  Google Scholar 

  76. Lipinski MM, Yuan J (2004) Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharm 4:85–90

    Article  CAS  Google Scholar 

  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 22:623–633

    Article  CAS  PubMed  Google Scholar 

  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 21:333–345

    Article  CAS  PubMed  Google Scholar 

  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 18:541–552

    Article  CAS  PubMed  Google Scholar 

  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 113:457–468

    Article  CAS  PubMed  Google Scholar 

  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 57:505–512

    Article  PubMed  Google Scholar 

  82. Albrecht M, Golatta M, Wullner U, Lengauer T (2004) Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem 271:3155–3170

    Article  CAS  PubMed  Google Scholar 

  83. He W, Parker R (2000) Functions of Lsm proteins in mRNA degradation and splicing. Curr Opin Cell Biol 12:346–350

    Article  CAS  PubMed  Google Scholar 

  84. Shibata H, Huynh DP, Pulst SM (2000) A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet 9:1303–1313

    Article  CAS  PubMed  Google Scholar 

  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 22:905–912

    Article  CAS  PubMed  Google Scholar 

  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 26:191–194

    Article  CAS  PubMed  Google Scholar 

  87. Lin X, Ashizawa T (2005) Recent progress in spinocerebellar ataxia type-10 (SCA10). Cerebellum 4:37–42

    Article  CAS  PubMed  Google Scholar 

  88. Coates JC (2003) Armadillo repeat proteins: beyond the animal kingdom. Trends Cell Biol 13:463–471

    Article  CAS  PubMed  Google Scholar 

  89. Sontag E (2001) Protein phosphatase 2A: the Trojan horse of cellular signaling. Cell Signal 13:7–16

    Article  CAS  PubMed  Google Scholar 

  90. Lim J, Lu KP (2005) Pinning down phosphorylated tau and tauopathies. Biochim Biophys Acta 1739:311–322

    CAS  PubMed  Google Scholar 

  91. Waters MF, Pulst SM (2008) Sca13. Cerebellum 7:165–169

    Article  CAS  PubMed  Google Scholar 

  92. Newton AC (2001) Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101:2353–2364

    Article  CAS  PubMed  Google Scholar 

  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 110:675–689

    Article  CAS  PubMed  Google Scholar 

  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 75:1263–1271

    Article  CAS  PubMed  Google Scholar 

  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 121:2339–2349

    Article  CAS  PubMed  Google Scholar 

  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 35:25–38

    Article  CAS  PubMed  Google Scholar 

  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 33:81–88

    Article  CAS  PubMed  Google Scholar 

  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 77:280–296

    Article  CAS  PubMed  Google Scholar 

  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 59:392–399

    CAS  PubMed  Google Scholar 

  100. Manto M, Marmolino D (2009) Cerebellar ataxias. Curr Opin Neurol 22:419–429

    Article  PubMed  Google Scholar 

  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 24:1111–1124

    Article  PubMed  Google Scholar 

  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:e182

    Article  PubMed  CAS  Google Scholar 

  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 10:816–820

    Article  CAS  PubMed  Google Scholar 

  104. Muchowski PJ, Wacker JL (2005) Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 6:11–22

    Article  CAS  PubMed  Google Scholar 

  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 9:2811–2820

    Article  CAS  PubMed  Google Scholar 

  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 97:6739–6744

    Article  CAS  PubMed  Google Scholar 

  107. Sanchez I, Mahlke C, Yuan J (2003) Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421:373–379

    Article  CAS  PubMed  Google Scholar 

  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 10:88–99

    Article  CAS  PubMed  Google Scholar 

  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 10:148–154

    Article  CAS  PubMed  Google Scholar 

  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 99:16400–16406

    Article  CAS  PubMed  Google Scholar 

  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 102:892–897

    Article  CAS  PubMed  Google Scholar 

  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 10:402–405

    Article  CAS  PubMed  Google Scholar 

  113. Rimoldi M, Servadio A, Zimarino V (2001) Analysis of heat shock transcription factor for suppression of polyglutamine toxicity. Brain Res Bull 56:353–362

    Article  CAS  PubMed  Google Scholar 

  114. Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918

    Article  CAS  PubMed  Google Scholar 

  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 22:8942–8950

    CAS  PubMed  Google Scholar 

  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 8:143–149

    Article  CAS  PubMed  Google Scholar 

  117. Shults CW (2003) Coenzyme Q10 in neurodegenerative diseases. Curr Med Chem 10:1917–1921

    Article  CAS  PubMed  Google Scholar 

  118. Ryu H, Rosas HD, Hersch SM, Ferrante RJ (2005) The therapeutic role of creatine in Huntington's disease. Pharmacol Ther 108:193–207

    Article  CAS  PubMed  Google Scholar 

  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 99:10671–10676

    Article  CAS  PubMed  Google Scholar 

  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 399:263–267

    Article  CAS  PubMed  Google Scholar 

  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 6:797–801

    Article  CAS  PubMed  Google Scholar 

  122. Lesort M, Lee M, Tucholski J, Johnson GV (2003) Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J Biol Chem 278:3825–3830

    Article  CAS  PubMed  Google Scholar 

  123. Gauthier S (2009) Dimebon improves cognitive function in people with mild to moderate Alzheimer's disease. Evid Based Ment Health 12:21

    Article  PubMed  Google Scholar 

  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 CD006455

  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 322:709–720

    Article  CAS  PubMed  Google Scholar 

  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 171:535–541

    Article  PubMed  Google Scholar 

  127. Dokmanovic M, Marks PA (2005) Prospects: Histone deacetylase inhibitors. J Cell Biochem 96:293–304

    Article  CAS  PubMed  Google Scholar 

  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 105:15564–15569

    Article  CAS  PubMed  Google Scholar 

  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)

  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 105:1291–1296

    Article  CAS  PubMed  Google Scholar 

  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 50:134–141

    Article  CAS  PubMed  Google Scholar 

  132. Leinninger GM, Feldman EL (2005) Insulin-like growth factors in the treatment of neurological disease. Endocr Devel 9:135–159

    Article  CAS  Google Scholar 

  133. Gage FH (2002) Neurogenesis in the adult brain. J Neurosci 22:612–613

    CAS  PubMed  Google Scholar 

  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 66:1717–1720

    Article  CAS  PubMed  Google Scholar 

  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 71:486–492

    Article  CAS  PubMed  Google Scholar 

  136. Lastres-Becker I, Rub U, Auburger G (2008) Spinocerebellar ataxia 2 (SCA2). Cerebellum 7:115–124

    Article  CAS  PubMed  Google Scholar 

  137. Garden GA, La Spada AR (2008) Molecular pathogenesis and cellular pathology of spinocerebellar ataxia type 7 neurodegeneration. Cerebellum 7:138–149

    Article  CAS  PubMed  Google Scholar 

  138. Higgins JJ, Pho LT, Ide SE, Nee LE, Polymeropoulos MH (1997) Evidence for a new spinocerebellar ataxia locus. Mov Disord 12:412–417

    Article  CAS  PubMed  Google Scholar 

  139. Johnson J, Wood N, Giunti P, Houlden H (2008) Clinical and genetic analysis of spinocerebellar ataxia type 11. Cerebellum 7:159–164

    Article  CAS  PubMed  Google Scholar 

  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 57:96–100

    CAS  PubMed  Google Scholar 

  141. Stevanin G, Brice A (2008) Spinocerebellar ataxia 17 (SCA17) and Huntington's disease-like 4 (HDL4). Cerebellum 7:170–178

    Article  CAS  PubMed  Google Scholar 

  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 56:234–238

    CAS  PubMed  Google Scholar 

  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 111:388–393

    Article  CAS  PubMed  Google Scholar 

  144. Schelhaas HJ, van de Warrenburg BP (2005) Clinical, psychological, and genetic characteristics of spinocerebellar ataxia type 19 (SCA19). Cerebellum 4:51–54

    Article  CAS  PubMed  Google Scholar 

  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 17:3847–3853

    Article  CAS  PubMed  Google Scholar 

  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 7:179–183

    Article  CAS  PubMed  Google Scholar 

  147. Chung MY, Lu YC, Cheng NC, Soong BW (2003) A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21–q23. Brain 126:1293–1299

    Article  PubMed  Google Scholar 

  148. Verbeek DS (2009) Spinocerebellar ataxia type 23: a genetic update. Cerebellum 8:104–107

    Article  CAS  PubMed  Google Scholar 

  149. Stevanin G, Broussolle E, Streichenberger N, Kopp N, Brice A, Durr A (2005) Spinocerebellar ataxia with sensory neuropathy (SCA25). Cerebellum 4:58–61

    Article  CAS  PubMed  Google Scholar 

  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 57:349–354

    Article  CAS  PubMed  Google Scholar 

  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 7:184–188

    Article  CAS  PubMed  Google Scholar 

  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 63:2288–2292

    CAS  PubMed  Google Scholar 

  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 80:408–411

    Article  CAS  PubMed  Google Scholar 

  154. Tsuji S (2002) Dentatorubral-pallidoluysian atrophy: clinical aspects and molecular genetics. Adv Neurol 89:231–239

    PubMed  Google Scholar 

  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 80:518–523

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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.

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Matilla-Dueñas, A., Sánchez, I., Corral-Juan, M. et al. Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias. Cerebellum 9, 148–166 (2010). https://doi.org/10.1007/s12311-009-0144-2

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