The Cerebellum

, Volume 13, Issue 2, pp 269–302 | Cite as

Consensus Paper: Pathological Mechanisms Underlying Neurodegeneration in Spinocerebellar Ataxias

  • A. Matilla-DueñasEmail author
  • T. Ashizawa
  • A. Brice
  • S. Magri
  • K. N. McFarland
  • M. Pandolfo
  • S. M. Pulst
  • O. Riess
  • D. C. Rubinsztein
  • J. Schmidt
  • T. Schmidt
  • D. R. Scoles
  • G. Stevanin
  • F. Taroni
  • B. R. Underwood
  • I. Sánchez
Consensus Paper


Intensive scientific research devoted in the recent years to understand the molecular mechanisms or neurodegeneration in spinocerebellar ataxias (SCAs) are identifying new pathways and targets providing new insights and a better understanding of the molecular pathogenesis in these diseases. In this consensus manuscript, the authors discuss their current views on the identified molecular processes causing or modulating the neurodegenerative phenotype in spinocerebellar ataxias with the common opinion of translating the new knowledge acquired into candidate targets for therapy. The following topics are discussed: transcription dysregulation, protein aggregation, autophagy, ion channels, the role of mitochondria, RNA toxicity, modulators of neurodegeneration and current therapeutic approaches. Overall point of consensus includes the common vision of neurodegeneration in SCAs as a multifactorial, progressive and reversible process, at least in early stages. Specific points of consensus include the role of the dysregulation of protein folding, transcription, bioenergetics, calcium handling and eventual cell death with apoptotic features of neurons during SCA disease progression. Unresolved questions include how the dysregulation of these pathways triggers the onset of symptoms and mediates disease progression since this understanding may allow effective treatments of SCAs within the window of reversibility to prevent early neuronal damage. Common opinions also include the need for clinical detection of early neuronal dysfunction, for more basic research to decipher the early neurodegenerative process in SCAs in order to give rise to new concepts for treatment strategies and for the translation of the results to preclinical studies and, thereafter, in clinical practice.


Aggregation Ataxia Autophagy Calcium Cerebellum Mitochondria Neurodegeneration Polyglutamine Purkinje cell Therapy Transcription dysregulation Neuronal death 



ATPase family member 3-like 2


Human atrophin-1 protein


Mouse ataxin


Human ataxin


Brain-derived neurotrophic factor


Codon that codes for glutamine


C. elegans cell death gene


Dark cell degeneration


Dentatorubral–pallidoluysian atrophy


Excitatory amino acid transporter 1


US Food and Drug Administration


Friedreich’s ataxia


Fragile X-associated tremor/ataxia syndrome


γ-Aminobutyric acid


Histone acetyltransferase


Huntington’s disease


Histone deacetylase


Heterogeneous nuclear ribonucleoprotein K


Inositol 1,4,5-triphosphate receptor type 1




Mammalian target of rapamycin


Neuronal intranuclear inclusions (bodies)


Purkinje cells




Human protein phosphatase 2, regulatory subunit B, beta


RNA-binding protein


Randomised, placebo-controlled trial


Reactive oxygen species


Spinocerebellar ataxias


TATA-binding protein


Ubiquitin–proteasome system


Voltage-gated ion channels



The authors acknowledge the following agencies for funding: the Spanish Ministry of Science and Innovation (BFU2008-00527/BMC to AM-D and IS); the Carlos III Health Institute (CP08/00027 to AM-D); the Iberoamerican Programme for Science, Technology and Development (CYTED; RIBERMOV, 210RT0390 to AM-D and IS); the European Commission (EUROSCA project, LHSM-CT-2004-503304 to AB, AM-D, DCR, GS and OR; the NEUROMICS project 7th PCRD-305121 to AB, AM-D, DCR, GS, IS, OR); the Fundació de la Marató de TV3 (Televisió de Catalunya, 100730 to AM-D and IS); the French Association “Connaitre les Syndrômes Cérébelleux”, the Verum Foundation (to GS); and the program “Investissements d’Avenir” (to AB and GS). TA is supported by the US National Institutes of Health (grant R01NS083564). DCR is funded by a Wellcome Trust Principal Fellowship, a Wellcome Trust/MRC Strategic Grant on Alzheimer’s disease and the Biomedical Research Unit in Dementia at Addenbrooke’s Hospital. Funding was obtained from the National Institutes of Health, R01NS033123 to S.M.P. and RC4NS073009 to SMP and DRS. FT was funded by Telethon-Italia (GGP09301), the Italian Ministry of Health (RF-2009-1539841) and ERA-Net E-Rare-2 JTC2011 (Euro-SCAR). Antoni Matilla-Dueñas is a Miguel Servet Investigator in Neurosciences of the Spanish National Health System.

We apologize to those research groups whose contributions could not be referred in this review due to space constraints.

Conflict of Interest

The authors declare no competing financial interests.


  1. 1.
    Orr H, Chung M-y, Banfi S, Kwiatkowski Jr TJ, Servadio A, Beaudet AL, et al. Expansion of an unstable trinucleotide (CAG) repeat in spinocerebellar ataxia type 1. Nat Genet. 1993;4:221–6.PubMedGoogle Scholar
  2. 2.
    Jacobi H, Bauer P, Giunti P, Labrum R, Sweeney MG, Charles P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology. 2011;77:1035–41.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Dohlinger S, Hauser TK, Borkert J, Luft AR, Schulz JB. Magnetic resonance imaging in spinocerebellar ataxias. Cerebellum. 2008;7:204–14.PubMedGoogle Scholar
  4. 4.
    Reetz K, Costa AS, Mirzazade S, Lehmann A, Juzek A, Rakowicz M, et al. Genotype-specific patterns of atrophy progression are more sensitive than clinical decline in SCA1, SCA3 and SCA6. Brain. 2013;136:905–17.PubMedGoogle Scholar
  5. 5.
    Manto MU. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum. 2005;4:2–6.PubMedGoogle Scholar
  6. 6.
    Schulz JB, Borkert J, Wolf S, Schmitz-Hubsch T, Rakowicz M, Mariotti C, et al. Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia types 1, 3 and 6. Neuroimage. 2010;49:158–68.PubMedGoogle Scholar
  7. 7.
    Scherzed W, Brunt ER, Heinsen H, de Vos RA, Seidel K, Burk K., et al. Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Cerebellum. 2012; 11:749–60.Google Scholar
  8. 8.
    Abraham MC, Lu Y, Shaham S. A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans. Dev Cell. 2007;12:73–86.PubMedGoogle Scholar
  9. 9.
    Yuan J, Kroemer G. Alternative cell death mechanisms in development and beyond. Genes Dev. 2010;24:2592–602.PubMedCentralPubMedGoogle Scholar
  10. 10.
    Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP, et al. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci. 2009;29:9148–62.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Chen X, Tang TS, Tu H, Nelson O, Pook M, Hammer R, et al. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci. 2008;28:12713–24.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Custer SK, Garden GA, Gill N, Rueb U, Libby RT, Schultz C, et al. Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat Neurosci. 2006;9:1302–11.PubMedGoogle Scholar
  13. 13.
    Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G. Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration. J Neurosci. 2009;29:9244–54.PubMedGoogle Scholar
  14. 14.
    Oppenheim RW, Flavell RA, Vinsant S, Prevette D, Kuan CY, Rakic P. Programmed cell death of developing mammalian neurons after genetic deletion of caspases. J Neurosci. 2001;21:4752–60.PubMedGoogle Scholar
  15. 15.
    Blum ES, Abraham MC, Yoshimura S, Lu Y, Shaham S. Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science. 2012;335:970–3.PubMedGoogle Scholar
  16. 16.
    Blum ES, Schwendeman AR, Shaham S. PolyQ disease: misfiring of a developmental cell death program? Trends Cell Biol. 2013;23:168–74.PubMedGoogle Scholar
  17. 17.
    Orr HT. Cell biology of spinocerebellar ataxia. J Cell Biol. 2012;197:167–77.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Chakrabarti L, Eng J, Ivanov N, Garden GA, La Spada AR. Autophagy activation and enhanced mitophagy characterize the Purkinje cells of pcd mice prior to neuronal death. Mol Brain. 2009;2:24.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Strahlendorf J, Box C, Attridge J, Diertien J, Finckbone V, Henne WM, et al. AMPA-induced dark cell degeneration of cerebellar Purkinje neurons involves activation of caspases and apparent mitochondrial dysfunction. Brain Res. 2003;994:146–59.PubMedGoogle Scholar
  20. 20.
    Barenberg P, Strahlendorf H, Strahlendorf J. Hypoxia induces an excitotoxic-type of dark cell degeneration in cerebellar Purkinje neurons. Neurosci Res. 2001;40:245–54.PubMedGoogle Scholar
  21. 21.
    Kasumu A, Bezprozvanny I. Deranged calcium signaling in Purkinje cells and pathogenesis in spinocerebellar ataxia 2 (SCA2) and other ataxias. Cerebellum. 2012;11:630–9.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Kasumu AW, Hougaard C, Rode F, Jacobsen TA, Sabatier JM, Eriksen BL, et al. Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. Chem Biol. 2012;19:1340–53.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Matilla-Dueñas A, Goold R, Giunti P. Molecular pathogenesis of spinocerebellar ataxias. Brain. 2006;129:1357–70.Google Scholar
  24. 24.
    Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9:885–94.PubMedGoogle Scholar
  25. 25.
    Friedman MJ, Shah AG, Fang ZH, Ward EG, Warren ST, Li S, et al. Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration. Nat Neurosci. 2007;10:1519–28.PubMedGoogle Scholar
  26. 26.
    Goold R, Hubank M, Hunt A, Holton J, Menon RP, Revesz T, et al. Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1. Hum Mol Genet. 2007;16:2122–34.PubMedGoogle Scholar
  27. 27.
    Crespo-Barreto J, Fryer JD, Shaw CA, Orr HT, Zoghbi HY. Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. PLoS Genet. 2010;6:e1001021.PubMedCentralPubMedGoogle Scholar
  28. 28.
    Matilla-Dueñas A, Sanchez I, Corral-Juan M, Davalos A, Alvarez R, Latorre P. Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias. Cerebellum. 2010;9:148–66.PubMedGoogle Scholar
  29. 29.
    Orr HT. Nuclear ataxias. Cold Spring Harb Perspect Biol. 2010;2:a000786.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Matilla-Dueñas A. The ever expanding spinocerebellar ataxias. Editorial. Cerebellum. 2012;11:821–7.PubMedGoogle Scholar
  31. 31.
    Sanchez I, Piñol P, Corral-Juan M, Pandolfo M, Matilla-Dueñas A. A novel function of Ataxin-1 in the modulation of PP2A activity is dysregulated in the spinocerebellar ataxia type 1. Hum Mol Genet. 2013;22:3425–37.PubMedGoogle Scholar
  32. 32.
    McCullough SD, Grant PA. Histone acetylation, acetyltransferases, and ataxia—alteration of histone acetylation and chromatin dynamics is implicated in the pathogenesis of polyglutamine-expansion disorders. Adv Protein Chem Struct Biol. 2010;79:165–203.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Smith KT, Workman JL. Introducing the acetylome. Nat Biotechnol. 2009;27:917–9.PubMedGoogle Scholar
  34. 34.
    Matilla-Dueñas A, Goold R, Giunti P. Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. Cerebellum. 2008;7:106–14.PubMedGoogle Scholar
  35. 35.
    Mushegian AR, Bassett Jr DE, Boguski MS, Bork P, Koonin EV. Positionally cloned human disease genes: patterns of evolutionary conservation and functional motifs. Proc Natl Acad Sci U S A. 1997;94:5831–6.PubMedCentralPubMedGoogle Scholar
  36. 36.
    de Chiara C, Giannini C, Adinolfi S, de Boer J, Guida S, Ramos A, et al. The AXH module: an independently folded domain common to ataxin-1 and HBP1. FEBS Lett. 2003;551:107–12.PubMedGoogle Scholar
  37. 37.
    Chen YW, Allen MD, Veprintsev DB, Lowe J, Bycroft M. The structure of the AXH domain of spinocerebellar ataxin-1. J Biol Chem. 2004;279:3758–65.PubMedGoogle Scholar
  38. 38.
    de Chiara C, Menon RP, Adinolfi S, de Boer J, Ktistaki E, Kelly G, et al. The AXH domain adopts alternative folds the solution structure of HBP1 AXH. Structure (Camb). 2005;13:743–53.Google Scholar
  39. 39.
    Yue S, Serra HG, Zoghbi HY, Orr HT. The spinocerebellar ataxia type 1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tract. Hum Mol Genet. 2001;10:25–30.PubMedGoogle Scholar
  40. 40.
    Lim J, Hao T, Shaw C, Patel AJ, Szabo G, Rual JF, et al. A protein–protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell. 2006;125:801–14.PubMedGoogle Scholar
  41. 41.
    Matilla A, Koshy BT, Cummings CJ, Isobe T, Orr HT, Zoghbi HY. The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1. Nature. 1997;389:974–8.PubMedGoogle Scholar
  42. 42.
    Bowman AB, Lam YC, Jafar-Nejad P, Chen HK, Richman R, Samaco RC, et al. Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nat Genet. 2007;39:373–9.PubMedGoogle Scholar
  43. 43.
    Tong X, Gui H, Jin F, Heck BW, Lin P, Ma J, et al. Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway. EMBO Rep. 2011;12:428–35.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Lam YC, Bowman AB, Jafar-Nejad P, Lim J, Richman R, Fryer JD, et al. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell. 2006;127:1335–47.PubMedGoogle Scholar
  45. 45.
    Tsuda H, Jafar-Nejad H, Patel AJ, Sun Y, Chen HK, Rose MF, et al. The AXH domain of ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins. Cell. 2005;122:633–44.PubMedGoogle Scholar
  46. 46.
    Tsai CC, Kao HY, Mitzutani A, Banayo E, Rajan H, McKeown M, et al. Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proc Natl Acad Sci U S A. 2004;101:4047–52.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Okazawa H, Rich T, Chang A, Lin X, Waragai M, Kajikawa M, et al. Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron. 2002;34:701–13.PubMedGoogle Scholar
  48. 48.
    Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, et al. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. 2006;127:697–708.PubMedGoogle Scholar
  49. 49.
    Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE, et al. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature. 2008;452:713–8.PubMedCentralPubMedGoogle Scholar
  50. 50.
    de Chiara C, Menon RP, Strom M, Gibson TJ, Pastore A. Phosphorylation of S776 and 14-3-3 binding modulate ataxin-1 interaction with splicing factors. PLoS One. 2009;4:e8372.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, She WC, Luchak JM, Martinez P, et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature. 2000;408:101–6.PubMedGoogle Scholar
  52. 52.
    Mizutani A, Wang L, Rajan H, Vig PJ, Alaynick WA, Thaler JP, et al. Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J. 2005;24:3339–51.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Gehrking KM, Andresen JM, Duvick L, Lough J, Zoghbi HY, Orr HT. Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model. Hum Mol Genet. 2011;20:2204–12.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet. 2004;13:2535–43.PubMedGoogle Scholar
  55. 55.
    Ciani L, Salinas PC. WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci. 2005;6:351–62.PubMedGoogle Scholar
  56. 56.
    Glover JC, Renaud JS, Rijli FM. Retinoic acid and hindbrain patterning. J Neurobiol. 2006;66:705–25.PubMedGoogle Scholar
  57. 57.
    Fryer JD, Yu P, Kang H, Mandel-Brehm C, Carter AN, Crespo-Barreto J, et al. Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science. 2011;334:690–3.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Ralser M, Albrecht M, Nonhoff U, Lengauer T, Lehrach H, Krobitsch S. An integrative approach to gain insights into the cellular function of human ataxin-2. J Mol Biol. 2005;346:203–14.PubMedGoogle Scholar
  59. 59.
    Nonis D, Schmidt MH, van de Loo S, Eich F, Dikic I, Nowock J, et al. Ataxin-2 associates with the endocytosis complex and affects EGF receptor trafficking. Cell Signal. 2008;20:1725–39.PubMedGoogle Scholar
  60. 60.
    Lastres-Becker I, Rub U, Auburger G. Spinocerebellar ataxia 2 (SCA2). Cerebellum. 2008;7:115–24.PubMedGoogle Scholar
  61. 61.
    Satterfield TF, Pallanck LJ. Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes. Hum Mol Genet. 2006;15:2523–32.PubMedGoogle Scholar
  62. 62.
    Hallen L, Klein H, Stoschek C, Wehrmeyer S, Nonhoff U, Ralser M, et al. The KRAB-containing zinc-finger transcriptional regulator ZBRK1 activates SCA2 gene transcription through direct interaction with its gene product, ataxin-2. Hum Mol Genet. 2011;20:104–14.PubMedGoogle Scholar
  63. 63.
    Urrutia R. KRAB-containing zinc-finger repressor proteins. Genome Biol. 2003;4:231.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, Naruse S, et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet. 2000;26:29–36.PubMedGoogle Scholar
  65. 65.
    Takahashi J, Tanaka J, Arai K, Funata N, Hattori T, Fukuda T, et al. Recruitment of nonexpanded polyglutamine proteins to intranuclear aggregates in neuronal intranuclear hyaline inclusion disease. J Neuropathol Exp Neurol. 2001;60:369–76.PubMedGoogle Scholar
  66. 66.
    McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet. 2000;9:2197–202.PubMedGoogle Scholar
  67. 67.
    Chai Y, Shao J, Miller VM, Williams A, Paulson HL. Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. Proc Natl Acad Sci U S A. 2002;99:9310–5.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N. Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum Mol Genet. 2000;9:1795–803.PubMedGoogle Scholar
  69. 69.
    Evert BO, Araujo J, Vieira-Saecker AM, de Vos RA, Harendza S, Klockgether T, et al. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J Neurosci. 2006;26:11474–86.PubMedGoogle Scholar
  70. 70.
    Costa Mdo C, Paulson HL. Toward understanding Machado–Joseph disease. Prog Neurobiol. 2012;97:239–57.PubMedGoogle Scholar
  71. 71.
    Evert BO, Vogt IR, Vieira-Saecker AM, Ozimek L, de Vos RA, Brunt ER, et al. Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3. J Neuropathol Exp Neurol. 2003;62:1006–18.PubMedGoogle Scholar
  72. 72.
    Araujo J, Breuer P, Dieringer S, Krauss S, Dorn S, Zimmermann K, et al. FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3. Hum Mol Genet. 2011;20:2928–41.PubMedGoogle Scholar
  73. 73.
    Helmlinger D, Hardy S, Abou-Sleymane G, Eberlin A, Bowman AB, Gansmüller A, et al. Glutamine-expanded ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction. PLoS Biol. 2006;4:e67.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Samara NL, Wolberger C. A new chapter in the transcription SAGA. Curr Opin Struct Biol. 2011;21:767–74.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Chen YC, Gatchel JR, Lewis RW, Mao CA, Grant PA, Zoghbi HY, et al. Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model. Hum Mol Genet. 2011;21:394–405.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Koide R, Kobayashi S, Shimohata T, Ikeuchi T, Maruyama M, Saito M, et al. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet. 1999;8:2047–53.PubMedGoogle Scholar
  77. 77.
    Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet. 2001;10:1441–8.PubMedGoogle Scholar
  78. 78.
    Kalmar B, Greensmith L. Induction of heat shock proteins for protection against oxidative stress. Adv Drug Deliv Rev. 2009;61:310–8.PubMedGoogle Scholar
  79. 79.
    Williams AJ, Paulson HL. Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci. 2008;31:521–8.PubMedCentralPubMedGoogle Scholar
  80. 80.
    Arawaka S, Machiya Y, Kato T. Heat shock proteins as suppressors of accumulation of toxic prefibrillar intermediates and misfolded proteins in neurodegenerative diseases. Curr Pharm Biotechnol. 2010;11:158–66.PubMedGoogle Scholar
  81. 81.
    Sajjad MU, Samson B, Wyttenbach A. Heat shock proteins: therapeutic drug targets for chronic neurodegeneration? Curr Pharm Biotechnol. 2010;11:198–215.PubMedGoogle Scholar
  82. 82.
    Gautier T, Berges T, Tollervey D, Hurt E. Nucleolar KKE/D repeat proteins Nop56p and Nop58p interact with Nop1p and are required for ribosome biogenesis. Mol Cell Biol. 1997;17:7088–98.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Kobayashi H, Abe K, Matsuura T, Ikeda Y, Hitomi T, Akechi Y, et al. Expansion of intronic GGCCTG hexanucleotide repeat in NOP56 causes SCA36, a type of spinocerebellar ataxia accompanied by motor neuron involvement. Am J Hum Genet. 2011;89:121–30.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Zhang S, Xu L, Lee J, Xu T. Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell. 2002;108:45–56.PubMedGoogle Scholar
  85. 85.
    Wang L, Rajan H, Pitman JL, McKeown M, Tsai CC. Histone deacetylase-associating atrophin proteins are nuclear receptor corepressors. Genes Dev. 2006;20:525–30.PubMedCentralPubMedGoogle Scholar
  86. 86.
    Shen Y, Lee G, Choe Y, Zoltewicz JS, Peterson AS. Functional architecture of atrophins. J Biol Chem. 2007;282:5037–44.PubMedGoogle Scholar
  87. 87.
    Wang L, Tsai CC. Atrophin proteins: an overview of a new class of nuclear receptor corepressors. Nucl Recept Signal. 2008;6:e009.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Wood JD, Nucifora Jr FC, Duan K, Zhang C, Wang J, Kim Y, et al. Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription. J Cell Biol. 2000;150:939–48.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Napoletano F, Occhi S, Calamita P, Volpi V, Blanc E, Charroux B, et al. Polyglutamine atrophin provokes neurodegeneration in Drosophila by repressing fat. EMBO J. 2011;30:945–58.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci. 2000;3:157–63.PubMedGoogle Scholar
  91. 91.
    Wiegert JS, Bading H. Activity-dependent calcium signaling and ERK-MAP kinases in neurons: a link to structural plasticity of the nucleus and gene transcription regulation. Cell Calcium. 2011;49:296–305.PubMedGoogle Scholar
  92. 92.
    Bilen J, Liu N, Bonini NM. A new role for microRNA pathways: modulation of degeneration induced by pathogenic human disease proteins. Cell Cycle. 2006;5:2835–8.PubMedGoogle Scholar
  93. 93.
    Karres JS, Hilgers V, Carrera I, Treisman J, Cohen SM. The conserved microRNA miR-8 tunes atrophin levels to prevent neurodegeneration in Drosophila. Cell. 2007;131:136–45.PubMedGoogle Scholar
  94. 94.
    Lee Y, Samaco RC, Gatchel JR, Thaller C, Orr HT, Zoghbi HY. miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesis. Nat Neurosci. 2008;11:1137–9.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Persengiev S, Kondova I, Otting N, Koeppen AH, Bontrop RE. Genome-wide analysis of miRNA expression reveals a potential role for miR-144 in brain aging and spinocerebellar ataxia pathogenesis. Neurobiol Aging. 2011;32(2316):e17–27.PubMedGoogle Scholar
  96. 96.
    DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997;277:1990–3.PubMedGoogle Scholar
  97. 97.
    Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997;19:333–44.PubMedGoogle Scholar
  98. 98.
    Skinner PJ, Koshy BT, Cummings CJ, Klement IA, Helin K, Servadio A, et al. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature. 1997;389:971–4.PubMedGoogle Scholar
  99. 99.
    Becher MW, Kotzuk JA, Sharp AH, Davies SW, Bates GP, Price DL, et al. Intranuclear neuronal inclusions in Huntington’s disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis. 1998;4:387–97.PubMedGoogle Scholar
  100. 100.
    Holmberg M, Duyckaerts C, Durr A, Cancel G, Gourfinkel-An I, Damier P, et al. Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet. 1998;7:913–8.PubMedGoogle Scholar
  101. 101.
    Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol. 1998;44:249–54.PubMedGoogle Scholar
  102. 102.
    Schmidt T, Landwehrmeyer GB, Schmitt I, Trottier Y, Auburger G, Laccone F, et al. An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol. 1998;8:669–79.PubMedGoogle Scholar
  103. 103.
    Huynh DP, Del Bigio MR, Ho DH, Pulst SM. Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer’s disease and spinocerebellar ataxia 2. Ann Neurol. 1999;45:232–41.PubMedGoogle Scholar
  104. 104.
    Koyano S, Uchihara T, Fujigasaki H, Nakamura A, Yagishita S, Iwabuchi K. Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study. Neurosci Lett. 1999;273:117–20.PubMedGoogle Scholar
  105. 105.
    Ishikawa K, Fujigasaki H, Saegusa H, Ohwada K, Fujita T, Iwamoto H, et al. Abundant expression and cytoplasmic aggregations of [alpha]1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. Hum Mol Genet. 1999;8:1185–93.PubMedGoogle Scholar
  106. 106.
    Munch C, Bertolotti A. Propagation of the prion phenomenon: beyond the seeding principle. J Mol Biol. 2012;421:491–8.PubMedGoogle Scholar
  107. 107.
    Freundt EC, Maynard N, Clancy EK, Roy S, Bousset L, Sourigues Y, et al. Neuron-to-neuron transmission of alpha-synuclein fibrils through axonal transport. Ann Neurol. 2012;72:517–24.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Yang W, Dunlap JR, Andrews RB, Wetzel R. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum Mol Genet. 2002;11:2905–17.PubMedGoogle Scholar
  109. 109.
    Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol. 2009;11:219–25.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ, et al. RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet. 2009;5:e1000600.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Seidel K, Siswanto S, Brunt ER, den Dunnen W, Korf HW, Rub U. Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012;124:1–21.PubMedGoogle Scholar
  112. 112.
    Houlden H, Johnson J, Gardner-Thorpe C, Lashley T, Hernandez D, Worth P, et al. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet. 2007;39:1434–6.PubMedGoogle Scholar
  113. 113.
    Perutz MF, Johnson T, Suzuki M, Finch JT. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci U S A. 1994;91:5355–8.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A. Expanded polyglutamine in the Machado–Joseph disease protein induces cell death in vitro and in vivo. Nat Genet. 1996;13:196–202.PubMedGoogle Scholar
  115. 115.
    Mangiarini L, Sathasivam K, Mahal A, Mott R, Seller M, Bates GP. Instability of highly expanded CAG repeats in mice transgenic for the Huntington’s disease mutation. Nat Genet. 1997;15:197–200.PubMedGoogle Scholar
  116. 116.
    Cowan KJ, Diamond MI, Welch WJ. Polyglutamine protein aggregation and toxicity are linked to the cellular stress response. Hum Mol Genet. 2003;12:1377–91.PubMedGoogle Scholar
  117. 117.
    Gusella JF, MacDonald ME. Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci. 2000;1:109–15.PubMedGoogle Scholar
  118. 118.
    Sieradzan KA, Mechan AO, Jones L, Wanker EE, Nukina N, Mann DM. Huntington’s disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Exp Neurol. 1999;156:92–9.PubMedGoogle Scholar
  119. 119.
    Garden GA, Libby RT, Fu YH, Kinoshita Y, Huang J, Possin DE, et al. Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous Purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. J Neurosci. 2002;22:4897–905.PubMedGoogle Scholar
  120. 120.
    Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, Ben-Haiem L, et al. A mutant ataxin-3 putative-cleavage fragment in brains of Machado–Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci. 2004;24:10266–79.PubMedGoogle Scholar
  121. 121.
    Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem. 1998;273:9158–67.PubMedGoogle Scholar
  122. 122.
    Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell. 2006;125:1179–91.PubMedGoogle Scholar
  123. 123.
    Haacke A, Hartl FU, Breuer P. Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem. 2007;282:18851–6.PubMedGoogle Scholar
  124. 124.
    Young JE, Gouw L, Propp S, Sopher BL, Taylor J, Lin A, et al. Proteolytic cleavage of ataxin-7 by caspase-7 modulates cellular toxicity and transcriptional dysregulation. J Biol Chem. 2007;282:30150–60.PubMedGoogle Scholar
  125. 125.
    Hubener J, Weber JJ, Richter C, Honold L, Weiss A, Murad F, et al. Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). Hum Mol Genet. 2013;22:508–18.PubMedGoogle Scholar
  126. 126.
    Simoes AT, Goncalves N, Koeppen A, Deglon N, Kugler S, Duarte CB, et al. Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado–Joseph disease. Brain. 2012;135:2428–39.PubMedGoogle Scholar
  127. 127.
    Masino L, Nicastro G, Menon RP, Dal Piaz F, Calder L, Pastore A. Characterization of the structure and the amyloidogenic properties of the Josephin domain of the polyglutamine-containing protein ataxin-3. J Mol Biol. 2004;344:1021–35.PubMedGoogle Scholar
  128. 128.
    Ellisdon AM, Thomas B, Bottomley SP. The two-stage pathway of ataxin-3 fibrillogenesis involves a polyglutamine-independent step. J Biol Chem. 2006;281:16888–96.PubMedGoogle Scholar
  129. 129.
    Hubener J, Vauti F, Funke C, Wolburg H, Ye Y, Schmidt T, et al. N-terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation. Brain. 2011;134:1925–42.PubMedGoogle Scholar
  130. 130.
    Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol. 1998;143:1457–70.PubMedCentralPubMedGoogle Scholar
  131. 131.
    Fujigasaki H, Uchihara T, Koyano S, Iwabuchi K, Yagishita S, Makifuchi T, et al. Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado–Joseph disease brains. Exp Neurol. 2000;165:248–56.PubMedGoogle Scholar
  132. 132.
    Uchihara T, Fujigasaki H, Koyano S, Nakamura A, Yagishita S, Iwabuchi K. Non-expanded polyglutamine proteins in intranuclear inclusions of hereditary ataxias—triple-labeling immunofluorescence study. Acta Neuropathol. 2001;102:149–52.PubMedGoogle Scholar
  133. 133.
    Chai Y, Wu L, Griffin JD, Paulson HL. The role of protein composition in specifying nuclear inclusion formation in polyglutamine disease. J Biol Chem. 2001;276:44889–97.PubMedGoogle Scholar
  134. 134.
    Zander C, Takahashi J, El Hachimi KH, Fujigasaki H, Albanese V, Lebre AS, et al. Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3. Hum Mol Genet. 2001;10:2569–79.PubMedGoogle Scholar
  135. 135.
    Schmidt T, Lindenberg KS, Krebs A, Schols L, Laccone F, Herms J, et al. Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol. 2002;51:302–10.PubMedGoogle Scholar
  136. 136.
    Verhoef LG, Lindsten K, Masucci MG, Dantuma NP. Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum Mol Genet. 2002;11:2689–700.PubMedGoogle Scholar
  137. 137.
    Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin–proteasome system by protein aggregation. Science. 2001;292:1552–5.PubMedGoogle Scholar
  138. 138.
    Waelter S, Boeddrich A, Lurz R, Scherzinger E, Lueder G, Lehrach H, et al. Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. Mol Biol Cell. 2001;12:1393–407.PubMedCentralPubMedGoogle Scholar
  139. 139.
    Zhou H, Cao F, Wang Z, Yu ZX, Nguyen HP, Evans J, et al. Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. J Cell Biol. 2003;163:109–18.PubMedCentralPubMedGoogle Scholar
  140. 140.
    Petroi D, Popova B, Taheri-Talesh N, Irniger S, Shahpasandzadeh H, Zweckstetter M, et al. Aggregate clearance of alpha-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome. J Biol Chem. 2012;287:27567–79.PubMedCentralPubMedGoogle Scholar
  141. 141.
    Sisodia SS. Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell. 1998;95:1–4.PubMedGoogle Scholar
  142. 142.
    Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y, et al. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain. 2005;128:659–70.PubMedGoogle Scholar
  143. 143.
    Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell. 1998;95:41–53.PubMedGoogle Scholar
  144. 144.
    Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. 1998;95:55–66.PubMedGoogle Scholar
  145. 145.
    Kretzschmar D, Tschape J, Bettencourt Da Cruz A, Asan E, Poeck B, Strauss R, et al. Glial and neuronal expression of polyglutamine proteins induce behavioral changes and aggregate formation in Drosophila. Glia. 2005;49:59–72.PubMedGoogle Scholar
  146. 146.
    Boy J, Schmidt T, Schumann U, Grasshoff U, Unser S, Holzmann C, et al. A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats. Neurobiol Dis. 2010;37:284–93.PubMedGoogle Scholar
  147. 147.
    Weiss A, Klein C, Woodman B, Sathasivam K, Bibel M, Regulier E, et al. Sensitive biochemical aggregate detection reveals aggregation onset before symptom development in cellular and murine models of Huntington’s disease. J Neurochem. 2008;104:846–58.PubMedGoogle Scholar
  148. 148.
    Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002;416:507–11.PubMedGoogle Scholar
  149. 149.
    Takahashi T, Nozaki K, Tsuji S, Nishizawa M, Onodera O. Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation. Neuroreport. 2005;16:295–9.PubMedGoogle Scholar
  150. 150.
    Chafekar SM, Wisen S, Thompson AD, Echeverria A, Walter GM, Evans CG, et al. Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation. ACS Chem Biol. 2012;7:1556–64.PubMedCentralPubMedGoogle Scholar
  151. 151.
    Bauer PO, Goswami A, Wong HK, Okuno M, Kurosawa M, Yamada M, et al. Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein. Nat Biotechnol. 2010;28:256–63.PubMedGoogle Scholar
  152. 152.
    Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain. 2010;133:93–104.PubMedCentralPubMedGoogle Scholar
  153. 153.
    Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007;8:931–7.PubMedGoogle Scholar
  154. 154.
    Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 2007;26:1749–60.PubMedCentralPubMedGoogle Scholar
  155. 155.
    Ravikumar B, Duden R, Rubinsztein DC. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet. 2002;11:1107–17.PubMedGoogle Scholar
  156. 156.
    Yang Z, Klionsky DJ. An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol. 2009;335:1–32.PubMedCentralPubMedGoogle Scholar
  157. 157.
    Ganley IG, du Lam H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284:12297–305.PubMedCentralPubMedGoogle Scholar
  158. 158.
    Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H, Meijer AJ. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem. 1997;243:240–6.PubMedGoogle Scholar
  159. 159.
    Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 2008;4:151–75.PubMedCentralPubMedGoogle Scholar
  160. 160.
    Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct. 1998;23:33–42.PubMedGoogle Scholar
  161. 161.
    Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90:1383–435.PubMedGoogle Scholar
  162. 162.
    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441:885–9.PubMedGoogle Scholar
  163. 163.
    Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441:880–4.PubMedGoogle Scholar
  164. 164.
    Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA, et al. Alpha-synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol. 2010;190:1023–37.PubMedCentralPubMedGoogle Scholar
  165. 165.
    Ju JS, Fuentealba RA, Miller SE, Jackson E, Piwnica-Worms D, Baloh RH, et al. Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol. 2009;187:875–88.PubMedCentralPubMedGoogle Scholar
  166. 166.
    Fukuda T, Ewan L, Bauer M, Mattaliano RJ, Zaal K, Ralston E, et al. Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Ann Neurol. 2006;59:700–8.PubMedGoogle Scholar
  167. 167.
    Sanchez-Varo R, Trujillo-Estrada L, Sanchez-Mejias E, Torres M, Baglietto-Vargas D, Moreno-Gonzalez I, et al. Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus. Acta Neuropathol. 2012;123:53–70.PubMedCentralPubMedGoogle Scholar
  168. 168.
    Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, et al. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci. 2010;13:567–76.PubMedCentralPubMedGoogle Scholar
  169. 169.
    Durcan TM, Fon EA. Mutant ataxin-3 promotes the autophagic degradation of parkin. Autophagy. 2011;7:233–4.PubMedGoogle Scholar
  170. 170.
    Berger Z, Ravikumar B, Menzies FM, Oroz LG, Underwood BR, Pangalos MN, et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet. 2006;15:433–42.PubMedGoogle Scholar
  171. 171.
    Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. Alpha-synuclein is degraded by both autophagy and the proteasome. J Biol Chem. 2003;278:25009–13.PubMedGoogle Scholar
  172. 172.
    Lunemann JD, Schmidt J, Schmid D, Barthel K, Wrede A, Dalakas MC, et al. Beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis. Ann Neurol. 2007;61:476–83.PubMedGoogle Scholar
  173. 173.
    Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, et al. Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nat Chem Biol. 2008;4:295–305.PubMedCentralPubMedGoogle Scholar
  174. 174.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36:585–95.PubMedGoogle Scholar
  175. 175.
    Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and tau: effects on cognitive impairments. J Biol Chem. 2010;285:13107–20.PubMedCentralPubMedGoogle Scholar
  176. 176.
    Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One. 2010;5:e9979.PubMedCentralPubMedGoogle Scholar
  177. 177.
    Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. J Neurosci. 2009;29:13578–88.PubMedCentralPubMedGoogle Scholar
  178. 178.
    Bilen J, Bonini NM. Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLoS Genet. 2007;3:1950–64.PubMedGoogle Scholar
  179. 179.
    Yamamoto K, Seki T, Adachi N, Takahashi T, Tanaka S, Hide I, et al. Mutant protein kinase C gamma that causes spinocerebellar ataxia type 14 (SCA14) is selectively degraded by autophagy. Genes Cells. 2010;15:425–38.PubMedGoogle Scholar
  180. 180.
    Yu X, Ajayi A, Boga NR, Strom AL. Differential degradation of full-length and cleaved ataxin-7 fragments in a novel stable inducible SCA7 model. J Mol Neurosci. 2012;47:219–33.PubMedCentralPubMedGoogle Scholar
  181. 181.
    Mookerjee S, Papanikolaou T, Guyenet SJ, Sampath V, Lin A, Vitelli C, et al. Posttranslational modification of ataxin-7 at lysine 257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment. J Neurosci. 2009;29:15134–44.PubMedCentralPubMedGoogle Scholar
  182. 182.
    Nascimento-Ferreira I, Santos-Ferreira T, Sousa-Ferreira L, Auregan G, Onofre I, Alves S, et al. Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado–Joseph disease. Brain. 2011;134:1400–15.PubMedGoogle Scholar
  183. 183.
    Grewer C, Rauen T. Electrogenic glutamate transporters in the CNS: molecular mechanism, pre-steady-state kinetics, and their impact on synaptic signaling. J Membr Biol. 2005;203:1–20.PubMedCentralPubMedGoogle Scholar
  184. 184.
    Ramamoorthy S, Leibach FH, Mahesh VB, Ganapathy V. Active transport of dopamine in human placental brush-border membrane vesicles. Am J Physiol. 1992;262:C1189–96.PubMedGoogle Scholar
  185. 185.
    Fahlke C. Molecular mechanisms of ion conduction in ClC-type chloride channels: lessons from disease-causing mutations. Kidney Int. 2000;57:780–6.PubMedGoogle Scholar
  186. 186.
    Thakker RV. Chloride channels in renal disease. Adv Nephrol Necker Hosp. 1999;29:289–98.PubMedGoogle Scholar
  187. 187.
    Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997;15:62–9.PubMedGoogle Scholar
  188. 188.
    Pulst SM, Santos N, Wang D, Yang H, Huynh D, Velazquez L, et al. Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset. Brain. 2005;128:2297–303.PubMedGoogle Scholar
  189. 189.
    Geschwind DH, Perlman S, Figueroa KP, Karrim J, Baloh RW, Pulst SM. Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations. Neurology. 1997;49:1247–51.PubMedGoogle Scholar
  190. 190.
    Baloh RW. Episodic ataxias 1 and 2. Handb Clin Neurol. 2012;103:595–602.PubMedGoogle Scholar
  191. 191.
    Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, et al. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Genet. 1997;6:1973–8.PubMedGoogle Scholar
  192. 192.
    Denier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A, et al. High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology. 1999;52:1816–21.PubMedGoogle Scholar
  193. 193.
    Walter JT, Alvina K, Womack MD, Chevez C, Khodakhah K. Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci. 2006;9:389–97.PubMedGoogle Scholar
  194. 194.
    Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, et al. Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. Proc Natl Acad Sci U S A. 2008;105:11987–92.PubMedCentralPubMedGoogle Scholar
  195. 195.
    Tonelli A, D‘Angelo MG, Salati R, Villa L, Germinasi C, Frattini T, et al. Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene. J Neurol Sci. 2006;241:13–7.PubMedGoogle Scholar
  196. 196.
    Jen J, Wan J, Graves M, Yu H, Mock AF, Coulin CJ, et al. Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology. 2001;57:1843–8.PubMedGoogle Scholar
  197. 197.
    Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, et al. Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci U S A. 2002;99:13284–9.PubMedCentralPubMedGoogle Scholar
  198. 198.
    Mullner C, Broos LA, van den Maagdenberg AM, Striessnig J. Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter Cav2.1 Ca2+ channel gating: evidence for beta-subunit isoform-specific effects. J Biol Chem. 2004;279:51844–50.PubMedGoogle Scholar
  199. 199.
    Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med. 2001;345:17–24.PubMedGoogle Scholar
  200. 200.
    Waters MF, Fee D, Figueroa KP, Nolte D, Muller U, Advincula J, et al. An autosomal dominant ataxia maps to 19q13: allelic heterogeneity of SCA13 or novel locus? Neurology. 2005;65:1111–3.PubMedGoogle Scholar
  201. 201.
    Herman-Bert A, Stevanin G, Netter JC, Rascol O, Brassat D, Calvas P, et al. Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation. Am J Hum Genet. 2000;67:229–35.PubMedCentralPubMedGoogle Scholar
  202. 202.
    Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JP, Nolte D, et al. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet. 2006;38:447–51.PubMedGoogle Scholar
  203. 203.
    Waters MF, Pulst SM. Sca13. Cerebellum. 2008;7:165–9.PubMedGoogle Scholar
  204. 204.
    Figueroa KP, Minassian NA, Stevanin G, Waters M, Garibyan V, Forlani S, et al. KCNC3: phenotype, mutations, channel biophysics—a study of 260 familial ataxia patients. Hum Mutat. 2010;31:191–6.PubMedCentralPubMedGoogle Scholar
  205. 205.
    Figueroa KP, Waters MF, Garibyan V, Bird TD, Gomez CM, Ranum LP, et al. Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13). PLoS One. 2011;6:e17811.PubMedCentralPubMedGoogle Scholar
  206. 206.
    Shakkottai VG, Chou CH, Oddo S, Sailer CA, Knaus HG, Gutman GA, et al. Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J Clin Invest. 2004;113:582–90.PubMedCentralPubMedGoogle Scholar
  207. 207.
    Figueroa KP, Chan P, Schols L, Tanner C, Riess O, Perlman SL, et al. Association of moderate polyglutamine tract expansions in the slow calcium-activated potassium channel type 3 with ataxia. Arch Neurol. 2001;58:1649–53.PubMedGoogle Scholar
  208. 208.
    Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA, Kramer P, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet. 1994;8:136–40.PubMedGoogle Scholar
  209. 209.
    D’Adamo MC, Imbrici P, Sponcichetti F, Pessia M. Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function. FASEB J. 1999;13:1335–45.PubMedGoogle Scholar
  210. 210.
    Jan LY, Jan YN. Voltage-gated potassium channels and the diversity of electrical signalling. J Physiol. 2012;590:2591–9.PubMedCentralPubMedGoogle Scholar
  211. 211.
    Rea R, Spauschus A, Eunson LH, Hanna MG, Kullmann DM. Variable K(+) channel subunit dysfunction in inherited mutations of KCNA1. J Physiol. 2002;538:5–23.PubMedCentralPubMedGoogle Scholar
  212. 212.
    Khavandgar S, Walter JT, Sageser K, Khodakhah K. Kv1 channels selectively prevent dendritic hyperexcitability in rat Purkinje cells. J Physiol. 2005;569:545–57.PubMedCentralPubMedGoogle Scholar
  213. 213.
    Herson PS, Virk M, Rustay NR, Bond CT, Crabbe JC, Adelman JP, et al. A mouse model of episodic ataxia type-1. Nat Neurosci. 2003;6:378–83.PubMedGoogle Scholar
  214. 214.
    Ishida S, Sakamoto Y, Nishio T, Baulac S, Kuwamura M, Ohno Y, et al. Kcna1-mutant rats dominantly display myokymia, neuromyotonia and spontaneous epileptic seizures. Brain Res. 2012;1435:154–66.PubMedGoogle Scholar
  215. 215.
    Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, et al. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012;72:859–69.PubMedGoogle Scholar
  216. 216.
    Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, et al. Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol. 2012;72:870–80.PubMedGoogle Scholar
  217. 217.
    Storey E, Gardner RJ. Spinocerebellar ataxia type 15. Handb Clin Neurol. 2012;103:561–5.PubMedGoogle Scholar
  218. 218.
    Iwaki A, Kawano Y, Miura S, Shibata H, Matsuse D, Li W, et al. Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16. J Med Genet. 2008;45:32–5.PubMedGoogle Scholar
  219. 219.
    van de Leemput J, Chandran J, Knight MA, Holtzclaw LA, Scholz S, Cookson MR, et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 2007;3:e108.PubMedCentralPubMedGoogle Scholar
  220. 220.
    Seal RP, Leighton BH, Amara SG. A model for the topology of excitatory amino acid transporters determined by the extracellular accessibility of substituted cysteines. Neuron. 2000;25:695–706.PubMedGoogle Scholar
  221. 221.
    Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology. 2005;65:529–34.PubMedGoogle Scholar
  222. 222.
    Seal RP, Shigeri Y, Eliasof S, Leighton BH, Amara SG. Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance. Proc Natl Acad Sci U S A. 2001;98:15324–9.PubMedCentralPubMedGoogle Scholar
  223. 223.
    Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012;44:1030–4.PubMedCentralPubMedGoogle Scholar
  224. 224.
    de Carvalho AP, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, et al. Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron. 2004;43:169–75.Google Scholar
  225. 225.
    Brashear A, Mink JW, Hill DF, Boggs N, McCall WV, Stacy MA, et al. ATP1A3 mutations in infants: a new rapid-onset dystonia-parkinsonism phenotype characterized by motor delay and ataxia. Dev Med Child Neurol. 2012;54:1065–7.PubMedCentralPubMedGoogle Scholar
  226. 226.
    Einholm AP, Toustrup-Jensen MS, Holm R, Andersen JP, Vilsen B. The rapid-onset dystonia parkinsonism mutation D923N of the Na+, K+-ATPase alpha3 isoform disrupts Na+ interaction at the third Na+ site. J Biol Chem. 2010;285:26245–54.PubMedCentralPubMedGoogle Scholar
  227. 227.
    Zanni G, Cali T, Kalscheuer VM, Ottolini D, Barresi S, Lebrun N, et al. Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis. Proc Natl Acad Sci U S A. 2012;109:14514–9.PubMedCentralPubMedGoogle Scholar
  228. 228.
    Hansen S, Pratap M, Otis T, Pulst SM. Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet. 2013; 22:271–83.Google Scholar
  229. 229.
    Hourez R, Servais L, Orduz D, Gall D, Millard I, de Kerchove d’Exaerde A, et al. Aminopyridines correct early dysfunction and delay neurodegeneration in a mouse model of spinocerebellar ataxia type 1. J Neurosci. 2011;31:11795–807.PubMedGoogle Scholar
  230. 230.
    Shakkottai VG, do Carmo Costa M, Dell’Orco JM, Sankaranarayanan A, Wulff H, Paulson HL. Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3. J Neurosci. 2011;31:13002–14.PubMedCentralPubMedGoogle Scholar
  231. 231.
    Shchelochkov OA, Cheung SW, Lupski JR. Genomic and clinical characteristics of microduplications in chromosome 17. Am J Med Genet. 2010;152A:1101–10.PubMedGoogle Scholar
  232. 232.
    Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K, et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet. 2000;26:191–4.PubMedGoogle Scholar
  233. 233.
    Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, et al. Spinocerebellar ataxia type 31 is associated with “inserted” penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet. 2009;85:544–57.PubMedCentralPubMedGoogle Scholar
  234. 234.
    Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57:127–30.PubMedGoogle Scholar
  235. 235.
    Wang JL, Wu YQ, Lei LF, Shen L, Jiang H, Zhou YF, et al. [Polynucleotide repeat expansion of nine spinocerebellar ataxia subtypes and dentatorubral–pallidoluysian atrophy in healthy Chinese Han population]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2010;27:501–5.PubMedGoogle Scholar
  236. 236.
    Wakamiya M, Matsuura T, Liu Y, Schuster GC, Gao R, Xu W, et al. The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10. Neurology. 2006;67:607–13.PubMedGoogle Scholar
  237. 237.
    Keren B, Jacquette A, Depienne C, Leite P, Durr A, Carpentier W, et al. Evidence against haploinsuffiency of human ataxin 10 as a cause of spinocerebellar ataxia type 10. Neurogenetics. 2010;11:273–4.PubMedGoogle Scholar
  238. 238.
    White MC, Gao R, Xu W, Mandal SM, Lim JG, Hazra TK, et al. Inactivation of hnRNP K by expanded intronic AUUCU repeat induces apoptosis via translocation of PKCdelta to mitochondria in spinocerebellar ataxia 10. PLoS Genet. 2010;6:e1000984.PubMedCentralPubMedGoogle Scholar
  239. 239.
    White M, Xia G, Gao R, Wakamiya M, Sarkar PS, McFarland K, et al. Transgenic mice with SCA10 pentanucleotide repeats show motor phenotype and susceptibility to seizure: a toxic RNA gain-of-function model. J Neurosci Res. 2012;90:706–14.PubMedCentralPubMedGoogle Scholar
  240. 240.
    Chan JY, Huang SM, Liu ST, Huang CH. The transactivation domain of heterogeneous nuclear ribonucleoprotein K overlaps its nuclear shuttling domain. Int J Biochem Cell Biol. 2008;40:2078–89.PubMedGoogle Scholar
  241. 241.
    Dejgaard K, Leffers H. Characterisation of the nucleic-acid-binding activity of KH domains. Different properties of different domains. Eur J Biochem. 1996;241:425–31.PubMedGoogle Scholar
  242. 242.
    Bomsztyk K, Denisenko O, Ostrowski J. hnRNP K: one protein multiple processes. Bioessays. 2004;26:629–38.PubMedGoogle Scholar
  243. 243.
    Schullery DS, Ostrowski J, Denisenko ON, Stempka L, Shnyreva M, Suzuki H, et al. Regulated interaction of protein kinase Cdelta with the heterogeneous nuclear ribonucleoprotein K protein. J Biol Chem. 1999;274:15101–9.PubMedGoogle Scholar
  244. 244.
    Brodie C, Blumberg PM. Regulation of cell apoptosis by protein kinase c delta. Apoptosis. 2003;8:19–27.PubMedGoogle Scholar
  245. 245.
    Sellier C, Rau F, Liu Y, Tassone F, Hukema RK, Gattoni R, et al. Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. EMBO J. 2010;29:1248–61.PubMedCentralPubMedGoogle Scholar
  246. 246.
    Mankodi A, Urbinati CR, Yuan QP, Moxley RT, Sansone V, Krym M, et al. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet. 2001;10:2165–70.PubMedGoogle Scholar
  247. 247.
    Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet. 2004;13:3079–88.PubMedGoogle Scholar
  248. 248.
    Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001;29:40–7.PubMedGoogle Scholar
  249. 249.
    Philips AV, Timchenko LT, Cooper TA. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science. 1998;280:737–41.PubMedGoogle Scholar
  250. 250.
    Charlet BN, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell. 2002;10:45–53.Google Scholar
  251. 251.
    Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10:35–44.PubMedGoogle Scholar
  252. 252.
    Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA. Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Invest. 2007;117:3952–7.PubMedCentralPubMedGoogle Scholar
  253. 253.
    McFarland KN, Liu J, Landrian I, Gao R, Sarkar PS, Raskin S, et al. Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability. Eur J Hum Genet. 2013;21:1272–6.PubMedGoogle Scholar
  254. 254.
    Ranum LP, Chung MY, Banfi S, Bryer A, Schut LJ, Ramesar R, et al. Molecular and clinical correlations in spinocerebellar ataxia type I: evidence for familial effects on the age at onset. Am J Hum Genet. 1994;55:244–52.PubMedCentralPubMedGoogle Scholar
  255. 255.
    Quan F, Janas J, Popovich BW. A novel CAG repeat configuration in the SCA1 gene: implications for the molecular diagnostics of spinocerebellar ataxia type 1. Hum Mol Genet. 1995;4:2411–3.PubMedGoogle Scholar
  256. 256.
    Matsuyama Z, Izumi Y, Kameyama M, Kawakami H, Nakamura S. The effect of CAT trinucleotide interruptions on the age at onset of spinocerebellar ataxia type 1 (SCA1). J Med Genet. 1999;36:546–8.PubMedCentralPubMedGoogle Scholar
  257. 257.
    Matsuura T, Fang P, Pearson CE, Jayakar P, Ashizawa T, Roa BB, et al. Interruptions in the expanded ATTCT repeat of spinocerebellar ataxia type 10: repeat purity as a disease modifier? Am J Hum Genet. 2006;78:125–9.PubMedCentralPubMedGoogle Scholar
  258. 258.
    Spaans F, Faber CG, Smeets HJ, Hofman PA, Braida C, Monckton DG, et al. Encephalopathic attacks in a family co-segregating myotonic dystrophy type 1, an intermediate Charcot–Marie–Tooth neuropathy and early hearing loss. J Neurol Neurosurg Psychiatry. 2009;80:1029–35.PubMedGoogle Scholar
  259. 259.
    Braida C, Stefanatos RK, Adam B, Mahajan N, Smeets HJ, Niel F, et al. Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients. Hum Mol Genet. 2010;19:1399–412.PubMedGoogle Scholar
  260. 260.
    Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466:1069–75.PubMedCentralPubMedGoogle Scholar
  261. 261.
    Sakai H, Yoshida K, Shimizu Y, Morita H, Ikeda S, Matsumoto N. Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan. Neurogenetics. 2010;11:409–15.PubMedCentralPubMedGoogle Scholar
  262. 262.
    Bonini NM, Gitler AD. Model organisms reveal insight into human neurodegenerative disease: ataxin-2 intermediate-length polyglutamine expansions are a risk factor for ALS. J Mol Neurosci. 2011;45:676–83.PubMedCentralPubMedGoogle Scholar
  263. 263.
    Corrado L, Mazzini L, Oggioni GD, Luciano B, Godi M, Brusco A, et al. ATXN-2 CAG repeat expansions are interrupted in ALS patients. Hum Genet. 2011;130:575–80.PubMedGoogle Scholar
  264. 264.
    Ishikawa K, Durr A, Klopstock T, Muller S, De Toffol B, Vidailhet M, et al. Pentanucleotide repeats at the spinocerebellar ataxia type 31 (SCA31) locus in Caucasians. Neurology. 2011;77:1853–5.PubMedGoogle Scholar
  265. 265.
    Yu Z, Zhu Y, Chen-Plotkin AS, Clay-Falcone D, McCluskey L, Elman L, et al. PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PLoS One. 2011;6:e17951.PubMedCentralPubMedGoogle Scholar
  266. 266.
    Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet. 1999;21:379–84.PubMedGoogle Scholar
  267. 267.
    Cho DH, Thienes CP, Mahoney SE, Analau E, Filippova GN, Tapscott SJ. Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol Cell. 2005;20:483–9.PubMedGoogle Scholar
  268. 268.
    Libby RT, Hagerman KA, Pineda VV, Lau R, Cho DH, Baccam SL, et al. CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genet. 2008;4:e1000257.PubMedCentralPubMedGoogle Scholar
  269. 269.
    Chung DW, Rudnicki DD, Yu L, Margolis RL. A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression. Hum Mol Genet. 2011;20:3467–77.PubMedCentralPubMedGoogle Scholar
  270. 270.
    Rudnicki DD, Pletnikova O, Vonsattel JP, Ross CA, Margolis RL. A comparison of Huntington disease and Huntington disease-like 2 neuropathology. J Neuropathol Exp Neurol. 2008;67:366–74.PubMedGoogle Scholar
  271. 271.
    Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS, et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet. 2006;38:758–69.PubMedGoogle Scholar
  272. 272.
    Ikeda Y, Daughters RS, Ranum LP. Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes. Cerebellum. 2008;7:150–8.PubMedGoogle Scholar
  273. 273.
    Chen IC, Lin HY, Lee GC, Kao SH, Chen CM, Wu YR, et al. Spinocerebellar ataxia type 8 larger triplet expansion alters histone modification and induces RNA foci. BMC Mol Biol. 2009;10:9.PubMedCentralPubMedGoogle Scholar
  274. 274.
    Batra R, Charizanis K, Swanson MS. Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum Mol Genet. 2010;19:R77–82.PubMedCentralPubMedGoogle Scholar
  275. 275.
    Mykowska A, Sobczak K, Wojciechowska M, Kozlowski P, Krzyzosiak WJ. CAG repeats mimic CUG repeats in the misregulation of alternative splicing. Nucleic Acids Res. 2011;39:8938–51.PubMedCentralPubMedGoogle Scholar
  276. 276.
    Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011;108:260–5.PubMedCentralPubMedGoogle Scholar
  277. 277.
    Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013;77:639–46.PubMedCentralPubMedGoogle Scholar
  278. 278.
    Pearson CE. Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLoS Genet. 2011;7:e1002018.PubMedCentralPubMedGoogle Scholar
  279. 279.
    Finsterer J. Mitochondrial ataxias. Can J Neurol Sci. 2009;36:543–53.PubMedGoogle Scholar
  280. 280.
    Di Donato S, Marmolino D, Taroni F. Mitochondrial disorders. In: Manto M, Schmahmann J, Rossi F, Gruol D, Koibuchi N, editors. Handbook of the cerebellum and cerebellar disorder. the Netherlands: Springer; 2013. p. 2269–311.Google Scholar
  281. 281.
    Montero R, Pineda M, Aracil A, Vilaseca MA, Briones P, Sanchez-Alcazar JA, et al. Clinical, biochemical and molecular aspects of cerebellar ataxia and coenzyme Q10 deficiency. Cerebellum. 2007;6:118–22.PubMedGoogle Scholar
  282. 282.
    Quinzii CM, Lopez LC, Naini A, DiMauro S, Hirano M. Human CoQ10 deficiencies. Biofactors. 2008;32:113–8.PubMedCentralPubMedGoogle Scholar
  283. 283.
    Spindler M, Beal MF, Henchcliffe C. Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr Dis Treat. 2009;5:597–610.PubMedCentralPubMedGoogle Scholar
  284. 284.
    Lagier-Tourenne C, Tazir M, Lopez LC, Quinzii CM, Assoum M, Drouot N, et al. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet. 2008;82:661–72.PubMedCentralPubMedGoogle Scholar
  285. 285.
    Gerards M, van den Bosch B, Calis C, Schoonderwoerd K, van Engelen K, Tijssen M, et al. Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy. Mitochondrion. 2010;10:510–5.PubMedGoogle Scholar
  286. 286.
    Lu S, Lu LY, Liu MF, Yuan QJ, Sham MH, Guan XY, et al. Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood. Neurobiol Dis. 2012;45:219–33.PubMedGoogle Scholar
  287. 287.
    Spinazzola A, Zeviani M. Disorders of nuclear-mitochondrial intergenomic signaling. Gene. 2005;354:162–8.PubMedGoogle Scholar
  288. 288.
    Copeland WC. Defects in mitochondrial DNA replication and human disease. Crit Rev Biochem Mol Biol. 2012;47:64–74.PubMedCentralPubMedGoogle Scholar
  289. 289.
    Kaguni LS. DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem. 2004;73:293–320.PubMedGoogle Scholar
  290. 290.
    Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008;29:E150–72.PubMedCentralPubMedGoogle Scholar
  291. 291.
    Hakonen AH, Heiskanen S, Juvonen V, Lappalainen I, Luoma PT, Rantamaki M, et al. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet. 2005;77:430–41.PubMedCentralPubMedGoogle Scholar
  292. 292.
    Milone M, Brunetti-Pierri N, Tang LY, Kumar N, Mezei MM, Josephs K, et al. Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord. 2008;18:626–32.PubMedGoogle Scholar
  293. 293.
    Nikali K, Suomalainen A, Saharinen J, Kuokkanen M, Spelbrink JN, Lonnqvist T, et al. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet. 2005;14:2981–90.PubMedGoogle Scholar
  294. 294.
    Sykora P, Croteau DL, Bohr VA, Wilson 3rd DM. Aprataxin localizes to mitochondria and preserves mitochondrial function. Proc Natl Acad Sci U S A. 2011;108:7437–42.PubMedCentralPubMedGoogle Scholar
  295. 295.
    Das BB, Dexheimer TS, Maddali K, Pommier Y. Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria. Proc Natl Acad Sci U S A. 2010;107:19790–5.PubMedCentralPubMedGoogle Scholar
  296. 296.
    Pandolfo M, Pastore A. The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J Neurol. 2009;256 Suppl 1:9–17.PubMedGoogle Scholar
  297. 297.
    Marmolino D. Friedreich’s ataxia: past, present and future. Brain Res Rev. 2011;67:311–30.PubMedGoogle Scholar
  298. 298.
    Martelli A, Napierala M, Puccio H. Understanding the genetic and molecular pathogenesis of Friedreich’s ataxia through animal and cellular models. Dis Model Mech. 2012;5:165–76.PubMedCentralPubMedGoogle Scholar
  299. 299.
    Martelli A, Wattenhofer-Donze M, Schmucker S, Bouvet S, Reutenauer L, Puccio H. Frataxin is essential for extramitochondrial Fe–S cluster proteins in mammalian tissues. Hum Mol Genet. 2007;16:2651–8.PubMedGoogle Scholar
  300. 300.
    Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science. 1997;276:1709–12.PubMedGoogle Scholar
  301. 301.
    Puccio H, Simon D, Cossee M, Criqui-Filipe P, Tiziano F, Melki J, et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe–S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet. 2001;27:181–6.PubMedGoogle Scholar
  302. 302.
    Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, et al. The Friedreich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet. 1999;8:425–30.PubMedGoogle Scholar
  303. 303.
    DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2008;31:91–123.PubMedGoogle Scholar
  304. 304.
    Schon EA, Przedborski S. Mitochondria: the next (neurode)generation. Neuron. 2011;70:1033–53.PubMedCentralPubMedGoogle Scholar
  305. 305.
    Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87:99–163.PubMedGoogle Scholar
  306. 306.
    Choo YS, Johnson GV, MacDonald M, Detloff PJ, Lesort M. Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum Mol Genet. 2004;13:1407–20.PubMedGoogle Scholar
  307. 307.
    Lipinski MM, Yuan J. Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharmacol. 2004;4:85–90.PubMedGoogle Scholar
  308. 308.
    Chou AH, Yeh TH, Kuo YL, Kao YC, Jou MJ, Hsu CY, et al. Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL. Neurobiol Dis. 2006;21:333–45.PubMedGoogle Scholar
  309. 309.
    Wang HL, Yeh TH, Chou AH, Kuo YL, Luo LJ, He CY, et al. Polyglutamine-expanded ataxin-7 activates mitochondrial apoptotic pathway of cerebellar neurons by upregulating Bax and downregulating Bcl-x(L). Cell Signal. 2006;18:541–52.PubMedGoogle Scholar
  310. 310.
    Laco MN, Oliveira CR, Paulson HL, Rego AC. Compromised mitochondrial complex II in models of Machado–Joseph disease. Biochim Biophys Acta. 1822;2012:139–49.Google Scholar
  311. 311.
    Ruan Q, Lesort M, MacDonald ME, Johnson GV. Striatal cells from mutant huntingtin knock-in mice are selectively vulnerable to mitochondrial complex II inhibitor-induced cell death through a non-apoptotic pathway. Hum Mol Genet. 2004;13:669–81.PubMedGoogle Scholar
  312. 312.
    Youle RJ, Karbowski M. Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol. 2005;6:657–63.PubMedGoogle Scholar
  313. 313.
    Chan DC. Mitochondria: dynamic organelles in disease, aging, and development. Cell. 2006;125:1241–52.PubMedGoogle Scholar
  314. 314.
    Liesa M, Palacin M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009;89:799–845.PubMedGoogle Scholar
  315. 315.
    Chan DC. Mitochondrial dynamics in disease. N Engl J Med. 2007;356:1707–9.PubMedGoogle Scholar
  316. 316.
    Chen H, McCaffery JM, Chan DC. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell. 2007;130:548–62.PubMedGoogle Scholar
  317. 317.
    Dagda RK, Merrill RA, Cribbs JT, Chen Y, Hell JW, Usachev YM, et al. The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission. J Biol Chem. 2008;283:36241–8.PubMedCentralPubMedGoogle Scholar
  318. 318.
    Lin CH, Chen CM, Hou YT, Wu YR, Hsieh-Li HM, Su MT, et al. The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression. Hum Genet. 2010;128:205–12.PubMedGoogle Scholar
  319. 319.
    Girard M, Lariviere R, Parfitt DA, Deane EC, Gaudet R, Nossova N, et al. Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS). Proc Natl Acad Sci U S A. 2012;109:1661–6.PubMedCentralPubMedGoogle Scholar
  320. 320.
    Wang YC, Lee CM, Lee LC, Tung LC, Hsieh-Li HM, Lee-Chen GJ, et al. Mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of spinocerebellar ataxia type 12 (SCA12). J Biol Chem. 2011;286:21742–54.PubMedCentralPubMedGoogle Scholar
  321. 321.
    Rugarli EI, Langer T. Mitochondrial quality control: a matter of life and death for neurons. EMBO J. 2012;31:1336–49.PubMedCentralPubMedGoogle Scholar
  322. 322.
    Di Bella D, Lazzaro F, Brusco A, Plumari M, Battaglia G, Pastore A, et al. Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28. Nat Genet. 2010;42:313–21.PubMedGoogle Scholar
  323. 323.
    Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell. 1998;93:973–83.PubMedGoogle Scholar
  324. 324.
    Tatsuta T, Langer T. Quality control of mitochondria: protection against neurodegeneration and ageing. EMBO J. 2008;27:306–14.PubMedCentralPubMedGoogle Scholar
  325. 325.
    Cagnoli C, Stevanin G, Brussino A, Barberis M, Mancini C, Margolis RL, et al. Missense mutations in the AFG3L2 proteolytic domain account for approximately 1.5% of European autosomal dominant cerebellar ataxias. Hum Mutat. 2010;31:1117–24.PubMedGoogle Scholar
  326. 326.
    Pierson TM, Adams D, Bonn F, Martinelli P, Cherukuri PF, Teer JK, et al. Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases. PLoS Genet. 2011;7:e1002325.PubMedCentralPubMedGoogle Scholar
  327. 327.
    Mariotti C, Brusco A, Di Bella D, Cagnoli C, Seri M, Gellera C, et al. Spinocerebellar ataxia type 28: a novel autosomal dominant cerebellar ataxia characterized by slow progression and ophthalmoparesis. Cerebellum. 2008;7:184–8.PubMedGoogle Scholar
  328. 328.
    Almajan ER, Richter R, Paeger L, Martinelli P, Barth E, Decker T, et al. AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival. J Clin Invest. 2012;122:4048–58.PubMedCentralPubMedGoogle Scholar
  329. 329.
    Maltecca F, De Stefani D, Cassina L, Consolato F, Wasilewski M, Scorrano L, et al. Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation. Hum Mol Genet. 2012;21:3858–70.PubMedCentralPubMedGoogle Scholar
  330. 330.
    Perlman SL. A review of Friedreich ataxia clinical trial results. J Child Neurol. 2012;27:1217–22.PubMedGoogle Scholar
  331. 331.
    Ilg W, Synofzik M, Brotz D, Burkard S, Giese MA, Schols L. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology. 2009;73:1823–30.PubMedGoogle Scholar
  332. 332.
    Ilg W, Brotz D, Burkard S, Giese MA, Schols L, Synofzik M. Long-term effects of coordinative training in degenerative cerebellar disease. Mov Disord. 2010;25:2239–46.PubMedGoogle Scholar
  333. 333.
    Soragni E, Herman D, Dent SY, Gottesfeld JM, Wells RD, Napierala M. Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia. Nucleic Acids Res. 2008;36:6056–65.PubMedCentralPubMedGoogle Scholar
  334. 334.
    Rai M, Soragni E, Jenssen K, Burnett R, Herman D, Coppola G, et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS One. 2008;3:e1958.PubMedCentralPubMedGoogle Scholar
  335. 335.
    Rai M, Soragni E, Chou CJ, Barnes G, Jones S, Rusche JR, et al. Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin upregulation in cells from Friedreich’s ataxia patients and in a mouse model. PLoS One. 2010;5:e8825.PubMedCentralPubMedGoogle Scholar
  336. 336.
    Herman D, Jenssen K, Burnett R, Soragni E, Perlman SL, Gottesfeld JM. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat Chem Biol. 2006;2:551–8.PubMedGoogle Scholar
  337. 337.
    Xu C, Soragni E, Chou CJ, Herman D, Plasterer HL, Rusche JR, et al. Chemical probes identify a role for histone deacetylase 3 in Friedreich’s ataxia gene silencing. Chem Biol. 2009;16:980–9.PubMedCentralPubMedGoogle Scholar
  338. 338.
    Shan G, Xu S, Jin P. FXTAS: a bad RNA and a hope for a cure. Expert Opin Biol Ther. 2008;8:249–53.PubMedCentralPubMedGoogle Scholar
  339. 339.
    Todd PK, Oh SY, Krans A, Pandey UB, Di Prospero NA, Min KT, et al. Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome. PLoS Genet. 2010;6:e1001240.PubMedCentralPubMedGoogle Scholar
  340. 340.
    Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT, et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004;10:816–20.PubMedGoogle Scholar
  341. 341.
    Scholefield J, Greenberg LJ, Weinberg MS, Arbuthnot PB, Abdelgany A, Wood MJ. Design of RNAi hairpins for mutation-specific silencing of ataxin-7 and correction of a SCA7 phenotype. PLoS One. 2009;4:e7232.PubMedCentralPubMedGoogle Scholar
  342. 342.
    Hu J, Gagnon KT, Liu J, Watts JK, Syeda-Nawaz J, Bennett CF, et al. Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs. Biol Chem. 2011;392:315–25.PubMedCentralPubMedGoogle Scholar
  343. 343.
    Fiszer A, Olejniczak M, Switonski PM, Wroblewska JP, Wisniewska-Kruk J, Mykowska A, et al. An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases. BMC Mol Biol. 2012;13:6.PubMedCentralPubMedGoogle Scholar
  344. 344.
    Tsou WL, Soong BW, Paulson HL, Rodriguez-Lebron E. Splice isoform-specific suppression of the Cav2.1 variant underlying spinocerebellar ataxia type 6. Neurobiol Dis. 2011;43:533–42.PubMedCentralPubMedGoogle Scholar
  345. 345.
    Bowers WJ, Breakefield XO, Sena-Esteves M. Genetic therapy for the nervous system. Hum Mol Genet. 2011;20:R28–41.PubMedCentralPubMedGoogle Scholar
  346. 346.
    Pandolfo M. Drug insight: antioxidant therapy in inherited ataxias. Nat Clin Pract Neurol. 2008;4:86–96.PubMedGoogle Scholar
  347. 347.
    Lynch DR, Willi SM, Wilson RB, Cotticelli MG, Brigatti KW, Deutsch EC, et al. A0001 in Friedreich ataxia: biochemical characterization and effects in a clinical trial. Mov Disord. 2012;27:1026–33.PubMedGoogle Scholar
  348. 348.
    Broccoletti T, Del Giudice E, Amorosi S, Russo I, Di Bonito M, Imperati F, et al. Steroid-induced improvement of neurological signs in ataxia–telangiectasia patients. Eur J Neurol. 2008;15:223–8.PubMedGoogle Scholar
  349. 349.
    Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10:83–98.PubMedGoogle Scholar
  350. 350.
    Gottesfeld JM, Pandolfo M. Development of histone deacetylase inhibitors as therapeutics for neurological disease. Future Neurol. 2009;4:775–84.PubMedCentralPubMedGoogle Scholar
  351. 351.
    Chou AH, Chen SY, Yeh TH, Weng YH, Wang HL. HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3. Neurobiol Dis. 2011;41:481–8.PubMedGoogle Scholar
  352. 352.
    Schorge S, van de Leemput J, Singleton A, Houlden H, Hardy J. Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling. Trends Neurosci. 2010;33:211–9.PubMedGoogle Scholar
  353. 353.
    Kasumu AW, Liang X, Egorova P, Vorontsova D, Bezprozvanny I. Chronic suppression of inositol 1,4,5-triphosphate receptor-mediated calcium signaling in cerebellar Purkinje cells alleviates pathological phenotype in spinocerebellar ataxia 2 mice. J Neurosci. 2012;32:12786–96.PubMedCentralPubMedGoogle Scholar
  354. 354.
    Stevanin G, Durr A, Brice A. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J Hum Genet. 2000;8:4–18.PubMedGoogle Scholar
  355. 355.
    Netravathi M, Pal PK, Purushottam M, Thennarasu K, Mukherjee M, Jain S. Spinocerebellar ataxias types 1, 2 and 3: age adjusted clinical severity of disease at presentation correlates with size of CAG repeat lengths. J Neurol Sci. 2009;277:83–6.PubMedGoogle Scholar
  356. 356.
    Ikeuchi T, Koide R, Tanaka H, Onodera O, Igarashi S, Takahashi H, et al. Dentatorubral-pallidoluysian atrophy: clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat. Ann Neurol. 1995;37:769–75.PubMedGoogle Scholar
  357. 357.
    Komure O, Sano A, Nishino N, Yamauchi N, Ueno S, Kondoh K, et al. DNA analysis in hereditary dentatorubral–pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation. Neurology. 1995;45:143–9.PubMedGoogle Scholar
  358. 358.
    Charles P, Camuzat A, Benammar N, Sellal F, Destee A, Bonnet AM, et al. Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism? Neurology. 2007;69:1970–5.PubMedGoogle Scholar
  359. 359.
    Modoni A, Contarino MF, Bentivoglio AR, Tabolacci E, Santoro M, Calcagni ML, et al. Prevalence of spinocerebellar ataxia type 2 mutation among Italian parkinsonian patients. Mov Disord. 2007;22:324–7.PubMedGoogle Scholar
  360. 360.
    Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, et al. Correlation between CAG repeat length and clinical features in Machado–Joseph disease. Am J Hum Genet. 1995;57:54–61.PubMedCentralPubMedGoogle Scholar
  361. 361.
    Durr A, Stevanin G, Cancel G, Duyckaerts C, Abbas N, Didierjean O, et al. Spinocerebellar ataxia 3 and Machado–Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol. 1996;39:490–9.PubMedGoogle Scholar
  362. 362.
    David G, Durr A, Stevanin G, Cancel G, Abbas N, Benomar A, et al. Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). Hum Mol Genet. 1998;7:165–70.PubMedGoogle Scholar
  363. 363.
    DeStefano AL, Cupples LA, Maciel P, Gaspar C, Radvany J, Dawson DM, et al. A familial factor independent of CAG repeat length influences age at onset of Machado–Joseph disease. Am J Hum Genet. 1996;59:119–27.PubMedCentralPubMedGoogle Scholar
  364. 364.
    van de Warrenburg BP, Hendriks H, Durr A, van Zuijlen MC, Stevanin G, Camuzat A, et al. Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch–French cohort. Ann Neurol. 2005;57:505–12.PubMedGoogle Scholar
  365. 365.
    Hayes S, Turecki G, Brisebois K, Lopes-Cendes I, Gaspar C, Riess O, et al. CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2). Hum Mol Genet. 2000;9:1753–8.PubMedGoogle Scholar
  366. 366.
    Chattopadhyay B, Ghosh S, Gangopadhyay PK, Das SK, Roy T, Sinha KK, et al. Modulation of age at onset in Huntington’s disease and spinocerebellar ataxia type 2 patients originated from eastern India. Neurosci Lett. 2003;345:93–6.PubMedGoogle Scholar
  367. 367.
    Jardim L, Silveira I, Pereira ML, do Ceu Moreira M, Mendonca P, Sequeiros J, et al. Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the Machado–Joseph disease (SCA3) phenotype. Acta Neurol Scand. 2003;107:211–4.PubMedGoogle Scholar
  368. 368.
    Latouche M, Lasbleiz C, Martin E, Monnier V, Debeir T, Mouatt-Prigent A, et al. A conditional pan-neuronal Drosophila model of spinocerebellar ataxia 7 with a reversible adult phenotype suitable for identifying modifier genes. J Neurosci. 2007;27:2483–92.PubMedGoogle Scholar
  369. 369.
    Lessing D, Bonini NM. Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila. PLoS Biol. 2008;6:e29.PubMedCentralPubMedGoogle Scholar
  370. 370.
    Vo SH, Butzlaff M, Pru SK, Ni Charthaigh RA, Karsten P, Lankes A, et al. Large-scale screen for modifiers of ataxin-3-derived polyglutamine-induced toxicity in Drosophila. PLoS One. 2012;7:e47452.Google Scholar
  371. 371.
    Fujigasaki H, Martin JJ, De Deyn PP, Camuzat A, Deffond D, Stevanin G, et al. CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia. Brain. 2001;124:1939–47.PubMedGoogle Scholar
  372. 372.
    Bruni AC, Takahashi-Fujigasaki J, Maltecca F, Foncin JF, Servadio A, Casari G, et al. Behavioral disorder, dementia, ataxia, and rigidity in a large family with TATA box-binding protein mutation. Arch Neurol. 2004;61:1314–20.PubMedGoogle Scholar
  373. 373.
    Rolfs A, Koeppen AH, Bauer I, Bauer P, Buhlmann S, Topka H, et al. Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann Neurol. 2003;54:367–75.PubMedGoogle Scholar
  374. 374.
    Emamian ES, Kaytor MD, Duvick LA, Zu T, Tousey SK, Zoghbi HY, et al. Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron. 2003;38:375–87.PubMedGoogle Scholar
  375. 375.
    Kaytor MD, Byam CE, Tousey SK, Stevens SD, Zoghbi HY, Orr HT. A cell-based screen for modulators of ataxin-1 phosphorylation. Hum Mol Genet. 2005;14:1095–105.PubMedGoogle Scholar
  376. 376.
    Janer A, Werner A, Takahashi-Fujigasaki J, Daret A, Fujigasaki H, Takada K, et al. SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7. Hum Mol Genet. 2010;19:181–95.PubMedGoogle Scholar
  377. 377.
    Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet. 1999;23:425–8.PubMedGoogle Scholar
  378. 378.
    Chan HY, Warrick JM, Gray-Board GL, Paulson HL, Bonini NM. Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet. 2000;9:2811–20.PubMedGoogle Scholar
  379. 379.
    Kazemi-Esfarjani P, Benzer S. Genetic suppression of polyglutamine toxicity in Drosophila. Science. 2000;287:1837–40.PubMedGoogle Scholar
  380. 380.
    Cummings CJ, Sun Y, Opal P, Antalffy B, Mestril R, Orr HT, et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum Mol Genet. 2001;10:1511–8.PubMedGoogle Scholar
  381. 381.
    Kimura Y, Koitabashi S, Kakizuka A, Fujita T. Initial process of polyglutamine aggregate formation in vivo. Genes Cells. 2001;6:887–97.PubMedGoogle Scholar
  382. 382.
    Higashiyama H, Hirose F, Yamaguchi M, Inoue YH, Fujikake N, Matsukage A, et al. Identification of ter94, Drosophila VCP, as a modulator of polyglutamine-induced neurodegeneration. Cell Death Differ. 2002;9:264–73.PubMedGoogle Scholar
  383. 383.
    van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ. Delaying the onset of Huntington’s in mice. Nature. 2000;404:721–2.PubMedGoogle Scholar
  384. 384.
    Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet. 1996;14:285–91.PubMedGoogle Scholar
  385. 385.
    Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996;14:269–76.PubMedGoogle Scholar
  386. 386.
    Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996;14:277–84.PubMedGoogle Scholar
  387. 387.
    Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, et al. CAG expansions in a novel gene for Machado–Joseph disease at chromosome 14q32.1. Nat Genet. 1994;8:221–7.PubMedGoogle Scholar
  388. 388.
    Hellenbroich Y, Pawlack H, Rub U, Schwinger E, Zuhlke C. Spinocerebellar ataxia type 4. Investigation of 34 candidate genes. J Neurol. 2005;252:1472–5.PubMedGoogle Scholar
  389. 389.
    Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC, et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet. 2006;38:184–90.PubMedGoogle Scholar
  390. 390.
    David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet. 1997;17:65–70.PubMedGoogle Scholar
  391. 391.
    Higgins JJ, Pho LT, Ide SE, Nee LE, Polymeropoulos MH. Evidence for a new spinocerebellar ataxia locus. Mov Disord. 1997;12:412–7.PubMedGoogle Scholar
  392. 392.
    O'Hearn E, Holmes SE, Margolis RL. Spinocerebellar ataxia type 12. Handb Clin Neurol. 2012;103:535–47.PubMedGoogle Scholar
  393. 393.
    Stevanin G, Durr A. Spinocerebellar ataxia 13 and 25. Handb Clin Neurol. 2012;103:549–53.PubMedGoogle Scholar
  394. 394.
    Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, et al. Missense mutations in the regulatory domain of PKCgamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet. 2003;72:839–49.PubMedCentralPubMedGoogle Scholar
  395. 395.
    Brkanac Z, Fernandez M, Matsushita M, Lipe H, Wolff J, Bird TD, et al. Autosomal dominant sensory/motor neuropathy with ataxia (SMNA): linkage to chromosome 7q22-q32. Am J Med Genet. 2002;114:450–7.PubMedGoogle Scholar
  396. 396.
    Brkanac Z, Spencer D, Shendure J, Robertson PD, Matsushita M, Vu T, et al. IFRD1 is a candidate gene for SMNA on chromosome 7q22-q23. Am J Hum Genet. 2009;84:692–7.PubMedCentralPubMedGoogle Scholar
  397. 397.
    Knight MA, Hernandez D, Diede SJ, Dauwerse HG, Rafferty I, van de Leemput J, et al. A duplication at chromosome 11q12.2-11q12.3 is associated with spinocerebellar ataxia type 20. Hum Mol Genet. 2008;17:3847–53.PubMedCentralPubMedGoogle Scholar
  398. 398.
    Vuillaume I, Devos D, Schraen-Maschke S, Dina C, Lemainque A, Vasseur F, et al. A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1. Ann Neurol. 2002;52:666–70.PubMedGoogle Scholar
  399. 399.
    Delplanque J, Devos D, Vuillaume I, De Becdelievre A, Vangelder E, Maurage CA, et al. Slowly progressive spinocerebellar ataxia with extrapyramidal signs and mild cognitive impairment (SCA21). Cerebellum. 2008;7:179–83.PubMedGoogle Scholar
  400. 400.
    Verbeek DS, van de Warrenburg BP, Wesseling P, Pearson PL, Kremer HP, Sinke RJ. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3. Brain. 2004;127:2551–7.PubMedGoogle Scholar
  401. 401.
    Hekman KE, Yu GY, Brown CD, Zhu H, Du X, Gervin K, et al. A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult. Hum Mol Genet. 2012;21:5472–83.PubMedCentralPubMedGoogle Scholar
  402. 402.
    Brusse E, de Koning I, Maat-Kievit A, Oostra BA, Heutink P, van Swieten JC. Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): a new phenotype. Mov Disord. 2006;21:396–401.PubMedGoogle Scholar
  403. 403.
    Mariotti C, Bella DD, Di Donato S, Taroni F. Spinocerebellar ataxia type 28. Handb Clin Neurol. 2012;103:575–9.PubMedGoogle Scholar
  404. 404.
    Dudding TE, Friend K, Schofield PW, Lee S, Wilkinson IA, Richards RI. Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus. Neurology. 2004;63:2288–92.PubMedGoogle Scholar
  405. 405.
    Storey E, Bahlo M, Fahey M, Sisson O, Lueck CJ, Gardner RJ. A new dominantly inherited pure cerebellar ataxia, SCA 30. J Neurol Neurosurg Psychiatry. 2009;80:408–11.PubMedGoogle Scholar
  406. 406.
    Jiang H, Zhu H-P, Gomez CM. SCA32: an autosomal dominant cerebellar ataxia with azoospermia maps to chromosome 7q32-q33. Abstract. Mov Disord. 2010;S192.Google Scholar
  407. 407.
    Giroux JM, Barbeau A. Erythrokeratodermia with ataxia. Arch Dermatol. 1972;106:183–8.PubMedGoogle Scholar
  408. 408.
    Wang JL, Yang X, Xia K, Hu ZM, Weng L, Jin X, et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain. 2010;133:3510–8.PubMedGoogle Scholar
  409. 409.
    Li M, Pang SY, Song Y, Kung MH, Ho SL, Sham PC. Whole exome sequencing identifies a novel mutation in the transglutaminase 6 gene for spinocerebellar ataxia in a Chinese family. Clin Genet. 2013;83:269–73.PubMedGoogle Scholar
  410. 410.
    Serrano-Munuera C, Corral-Juan M, Stevanin G, San Nicolas H, Roig C, Corral J, et al. New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32. JAMA Neurol. 2013;70:764–71.PubMedGoogle Scholar
  411. 411.
    Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K, et al. Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA). Nat Genet. 1994;6:9–13.PubMedGoogle Scholar
  412. 412.
    Nagafuchi S, Yanagisawa H, Sato K, Shirayama T, Ohsaki E, Bundo M, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet. 1994;6:14–8.PubMedGoogle Scholar
  413. 413.
    Yabe I, Sasaki H, Kikuchi S, Nonaka M, Moriwaka F, Tashiro K. Late onset ataxia phenotype in dentatorubro-pallidoluysian atrophy (DRPLA). J Neurol. 2002;249:432–6.PubMedGoogle Scholar
  414. 414.
    Amino T, Ishikawa K, Toru S, Ishiguro T, Sato N, Tsunemi T, et al. Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia. J Hum Genet. 2007;52:643–9.PubMedGoogle Scholar
  415. 415.
    Onodera Y, Aoki M, Mizuno H, Warita H, Shiga Y, Itoyama Y. Clinical features of chromosome 16q22.1 linked autosomal dominant cerebellar ataxia in Japanese. Neurology. 2006;67:1300–2.PubMedGoogle Scholar
  416. 416.
    Swartz BE, Burmeister M, Somers JT, Rottach KG, Bespalova IN, Leigh RJ. A form of inherited cerebellar ataxia with saccadic intrusions, increased saccadic speed, sensory neuropathy, and myoclonus. Ann N Y Acad Sci. 2002;956:441–4.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • A. Matilla-Dueñas
    • 1
    • 2
    Email author
  • T. Ashizawa
    • 6
  • A. Brice
    • 3
    • 4
    • 5
  • S. Magri
    • 12
  • K. N. McFarland
    • 6
  • M. Pandolfo
    • 7
  • S. M. Pulst
    • 8
  • O. Riess
    • 10
  • D. C. Rubinsztein
    • 9
  • J. Schmidt
    • 10
  • T. Schmidt
    • 10
  • D. R. Scoles
    • 8
  • G. Stevanin
    • 3
    • 4
    • 11
    • 5
  • F. Taroni
    • 12
  • B. R. Underwood
    • 13
  • I. Sánchez
    • 2
  1. 1.Health Sciences Research Institute Germans Trias i Pujol (IGTP)BadalonaSpain
  2. 2.Basic, Translational and Molecular Neurogenetics Research Unit in Neurosciences, Health Sciences Research Institute Germans Trias and Pujol (IGTP)Universitat Autònoma de Barcelona, BadalonaBarcelonaSpain
  3. 3.Institut du Cerveau et de la Moelle épinière, CHU Pitié-SalpêtrièreParisFrance
  4. 4.CR-ICM (Inserm/UPMC UMR_S 975, CNRS UMR 7225), CHU Pitié-SalpêtrièreParisFrance
  5. 5.APHP, Fédération de Génétique, CHU Pitié-SalpêtrièreParisFrance
  6. 6.McKnight Brain Institute and Department of NeurologyUniversity of FloridaGainesvilleUSA
  7. 7.Department of Neurology, Hôpital ErasmeUniversitéLibre de BruxellesBrusselsBelgium
  8. 8.Department of NeurologyUniversity of UtahSalt Lake CityUSA
  9. 9.Wellcome Trust/MRC Building, Addenbrooke’s HospitalCambridge Institute for Medical ResearchCambridgeUK
  10. 10.Institute of Medical Genetics & Applied Genomics and Centre for Rare Diseases (ZSE Tübingen)University of TuebingenTubingenGermany
  11. 11.Laboratoire de Neurogénétique, Ecole Pratique des Hautes Etudes, CHU Pitié-SalpêtrièreParisFrance
  12. 12.Unit of Genetics of Neurodegenerative and Metabolic DiseaseFondazione IRCCS Istituto Neurologico “Carlo Besta”MilanItaly
  13. 13.Department of Old Age PsychiatryBeechcroft, Fulbourn HospitalCambridgeUK

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