Skip to main content
SpringerLink
Log in

Molecular Mechanisms and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

  • Chapter
  • First Online:
Polyglutamine Disorders

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

Abstract

Spinocerebellar Ataxia type 7 (SCA7, OMIM # 164500) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia and blindness. SCA7 is part of the large family of autosomal dominant cerebellar ataxias (ADCAs), and was estimated to account for 1–11.7% of ADCAs in diverse populations. The frequency of SCA7 is higher where local founder effects were observed as in Scandinavia, Korea, South Africa and Mexico. SCA7 is pathomechanistically related to the group of CAG/polyglutamine (polyQ) expansion disorders, which includes other SCAs (1–3, 6 and 17), Huntington’s disease, spinal bulbar muscular atrophy and dentatorubro pallidoluysian atrophy. Two distinctive characteristics of SCA7 are the strong anticipation by which earlier onset and more severe symptoms are observed in successive generations of affected families, and the loss of visual acuity due to cone-rod dystrophy of the retina. The pathology is caused by an unstable CAG repeat expansion coding for a polyQ stretch in Ataxin-7 (ATXN7). PolyQ expansion in ATXN7 confers toxic properties and leads to selective neuronal degeneration in the cerebellum, the brain stem and the retina. Herein, we summarize the genetic, clinical and pathological features of SCA7 and review our current knowledge of pathomechanisms and preclinical studies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L et al (1995) Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 378:403–406

    Article  CAS  Google Scholar 

  2. David G, Durr A, Stevanin G, Cancel G, Abbas N, Benomar A, Belal S, Lebre AS, Abada-Bendib M, Grid D, Holmberg M, Yahyaoui M, Hentati F, Chkili T, Agid Y, Brice A (1998) Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). Hum Mol Genet 7:165–170

    Article  CAS  Google Scholar 

  3. van de Warrenburg BP, Frenken CW, Ausems MG, Kleefstra T, Sinke RJ, Knoers NV, Kremer HP (2001) Striking anticipation in spinocerebellar ataxia type 7: the infantile phenotype. J Neurol 248:911–914

    Article  Google Scholar 

  4. Michalik A, Martin JJ, Van Broeckhoven C (2004) Spinocerebellar ataxia type 7 associated with pigmentary retinal dystrophy. Eur J Hum Genet 12:2–15

    Article  CAS  Google Scholar 

  5. Monckton DG, Cayuela ML, Gould FK, Brock GJ, Silva R, Ashizawa T (1999) Very large (CAG) n DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males. Hum Mol Genet 8:2473–2478

    Article  CAS  Google Scholar 

  6. Giunti P, Stevanin G, Worth PF, David G, Brice A, Wood NW (1999) Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation. Am J Hum Genet 64:1594–1603

    Article  CAS  Google Scholar 

  7. Johansson J, Forsgren L, Sandgren O, Brice A, Holmgren G, Holmberg M (1998) Expanded CAG repeats in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect of CAG repeat length on the clinical manifestation. Hum Mol Genet 7:171–176

    Article  CAS  Google Scholar 

  8. Ansorge O, Giunti P, Michalik A, Van Broeckhoven C, Harding B, Wood N, Scaravilli F (2004) Ataxin-7 aggregation and ubiquitination in infantile SCA7 with 180 CAG repeats. Ann Neurol 56:448–452

    Article  CAS  Google Scholar 

  9. Benton CS, de Silva R, Rutledge SL, Bohlega S, Ashizawa T, Zoghbi HY (1998) Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 51:1081–1086

    Article  CAS  Google Scholar 

  10. Enevoldson TP, Sanders MD, Harding AE (1994) Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy. A clinical and genetic study of eight families. Brain J Neurol 117(3):445–460

    Article  Google Scholar 

  11. Trang H, Stanley SY, Thorner P, Faghfoury H, Schulze A, Hawkins C, Pearson CE, Yoon G (2014) Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7. JAMA Neurol

    Google Scholar 

  12. Whitney A, Lim M, Kanabar D, Lin JP (2007) Massive SCA7 expansion detected in a 7-month-old male with hypotonia, cardiomegaly, and renal compromise. Dev Med Child Neurol 49:140–143

    Article  Google Scholar 

  13. Alcauter S, Barrios FA, Diaz R, Fernandez-Ruiz J (2011) Gray and white matter alterations in spinocerebellar ataxia type 7: an in vivo DTI and VBM study. Neuroimage 55:1–7

    Article  CAS  Google Scholar 

  14. Bang OY, Lee PH, Kim SY, Kim HJ, Huh K (2004) Pontine atrophy precedes cerebellar degeneration in spinocerebellar ataxia 7: MRI-based volumetric analysis. J Neurol Neurosurg Psychiatry 75:1452–1456

    Article  CAS  Google Scholar 

  15. Horton LC, Frosch MP, Vangel MG, Weigel-DiFranco C, Berson EL, Schmahmann JD (2013) Spinocerebellar ataxia type 7: clinical course, phenotype-genotype correlations, and neuropathology. Cerebellum 12:176–193

    Article  Google Scholar 

  16. Martin J, Van Regemorter N, Del-Favero J, Lofgren A, Van Broeckhoven C (1999) Spinocerebellar ataxia type 7 (SCA7)—correlations between phenotype and genotype in one large Belgian family. J Neurol Sci 168:37–46

    Article  CAS  Google Scholar 

  17. Rub U, Brunt ER, Seidel K, Gierga K, Mooy CM, Kettner M, Van Broeckhoven C, Bechmann I, La Spada AR, Schols L, den Dunnen W, de Vos RA, Deller T (2008) Spinocerebellar ataxia type 7 (SCA7): widespread brain damage in an adult-onset patient with progressive visual impairments in comparison with an adult-onset patient without visual impairments. Neuropathol Appl Neurobiol 34:155–168

    Article  CAS  Google Scholar 

  18. Rub U, Brunt ER, Gierga K, Seidel K, Schultz C, Schols L, Auburger G, Heinsen H, Ippel PF, Glimmerveen WF, Wittebol-Post D, Arai K, Deller T, de Vos RA (2005) Spinocerebellar ataxia type 7 (SCA7): first report of a systematic neuropathological study of the brain of a patient with a very short expanded CAG-repeat. Brain Pathol 15:287–295

    Article  CAS  Google Scholar 

  19. Benomar A, Leguern E, Durr A, Ouhabi H, Stevanin G, Yahyaoui M, Chkili T, Agid Y, Brice A (1994) Autosomal-dominant cerebellar-ataxia with retinal degeneration (ADCA type-II) is genetically different from ADCA type-I. Ann Neurol 35:439–444

    Article  CAS  Google Scholar 

  20. Gouw LG, Digre KB, Harris CP, Haines JH, Ptacek LJ (1994) Autosomal-dominant cerebellar-ataxia with retinal degeneration—clinical, neuropathologic, and genetic-analysis of a large kindred. Neurology 44:1441–1447

    Article  CAS  Google Scholar 

  21. Martin JJ, Van Regemorter N, Krols L, Brucher JM, de Barsy T, Szliwowski H, Evrard P, Ceuterick C, Tassignon MJ, Smet-Dieleman H et al (1994) On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family. Acta Neuropathol (Berl) 88:277–286

    Article  CAS  Google Scholar 

  22. Aleman TS, Cideciyan AV, Volpe NJ, Stevanin G, Brice A, Jacobson SG (2002) Spinocerebellar ataxia type 7 (SCA7) shows a cone-rod dystrophy phenotype. Exp Eye Res 74:737–745

    Article  CAS  Google Scholar 

  23. Einum DD, Clark AM, Townsend JJ, Ptacek LJ, Fu YH (2003) A novel central nervous system-enriched spinocerebellar ataxia type 7 gene product. Arch Neurol 60:97–103

    Article  Google Scholar 

  24. Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C, Miguet L, Potier N, Van-Dorsselaer A, Wurtz JM, Mandel JL, Tora L, Devys D (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet 13:1257–1265

    Article  CAS  Google Scholar 

  25. Duncan CE, An MC, Papanikolaou T, Rugani C, Vitelli C, Ellerby LM (2013) Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model. Mol Neurodegener 8:42

    Article  Google Scholar 

  26. Janer A, Werner A, Takahashi-Fujigasaki J, Daret A, Fujigasaki H, Takada K, Duyckaerts C, Brice A, Dejean A, Sittler A (2010) SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7. Hum Mol Genet 19:181–195

    Article  CAS  Google Scholar 

  27. Cancel G, Duyckaerts C, Holmberg M, Zander C, Yvert G, Lebre AS, Ruberg M, Faucheux B, Agid Y, Hirsch E, Brice A (2000) Distribution of ataxin-7 in normal human brain and retina. Brain J Neurol 123(12):2519–2530

    Article  Google Scholar 

  28. Einum DD, Townsend JJ, Ptacek LJ, Fu YH (2001) Ataxin-7 expression analysis in controls and spinocerebellar ataxia type 7 patients. Neurogenetics 3:83–90

    Article  CAS  Google Scholar 

  29. Einum DD, Gouw L, MAtilla A, Townsend J, Fu YH, Ptacek LJ (1999) Expression analysis of ataxin-7 reveals restricted localization of an alternate isoform. Am J Hum Genet 65:A104–A104

    Google Scholar 

  30. Jonasson J, Strom AL, Hart P, Brannstrom T, Forsgren L, Holmberg M (2002) Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals. Acta Neuropathol 104:29–37

    Article  CAS  Google Scholar 

  31. Lindenberg KS, Yvert G, Muller K, Landwehrmeyer GB (2000) Expression analysis of ataxin-7 mRNA and protein in human brain: evidence for a widespread distribution and focal protein accumulation. Brain Pathol 10:385–394

    Article  CAS  Google Scholar 

  32. Mauger C, Del-Favero J, Ceuterick C, Lubke U, van Broeckhoven C, Martin J (1999) Identification and localization of ataxin-7 in brain and retina of a patient with cerebellar ataxia type II using anti-peptide antibody. Brain Res Mol Brain Res 74:35–43

    Article  CAS  Google Scholar 

  33. Strom AL, Jonasson J, Hart P, Brannstrom T, Forsgren L, Holmberg M (2002) Cloning and expression analysis of the murine homolog of the spinocerebellar ataxia type 7 (SCA7) gene. Gene 285:91–99

    Article  CAS  Google Scholar 

  34. Palhan VB, Chen S, Peng GH, Tjernberg A, Gamper AM, Fan Y, Chait BT, La Spada AR, Roeder RG (2005) Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci USA 102:8472–8477

    Article  CAS  Google Scholar 

  35. Sanders SL, Jennings J, Canutescu A, Link AJ, Weil PA (2002) Proteomics of the eukaryotic transcription machinery: identification of proteins associated with components of yeast TFIID by multidimensional mass spectrometry. Mol Cell Biol 22:4723–4738

    Article  CAS  Google Scholar 

  36. Scheel H, Tomiuk S, Hofmann K (2003) Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics. Hum Mol Genet 12:2845–2852

    Article  CAS  Google Scholar 

  37. Wyce A, Henry KW, Berger SL (2004) H2B ubiquitylation and de-ubiquitylation in gene activation. Novartis Found Symp 259:63–73; discussion 73–67, 163–169

    Google Scholar 

  38. Bonnet J, Wang CY, Baptista T, Vincent SD, Hsiao WC, Stierle M, Kao CF, Tora L, Devys D (2014) The SAGA coactivator complex acts on the whole transcribed genome and is required for RNA polymerase II transcription. Genes Dev 28:1999–2012

    Article  CAS  Google Scholar 

  39. Nakamura Y, Tagawa K, Oka T, Sasabe T, Ito H, Shiwaku H, La Spada AR, Okazawa H (2012) Ataxin-7 associates with microtubules and stabilizes the cytoskeletal network. Hum Mol Genet 21:1099–1110

    Article  CAS  Google Scholar 

  40. Kahle JJ, Gulbahce N, Shaw CA, Lim J, Hill DE, Barabasi AL, Zoghbi HY (2011) Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia. Hum Mol Genet 20:510–527

    Article  CAS  Google Scholar 

  41. Mohan RD, Dialynas G, Weake VM, Liu J, Martin-Brown S, Florens L, Washburn MP, Workman JL, Abmayr SM (2014) Loss of Drosophila ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration. Genes Dev 28:259–272

    Article  CAS  Google Scholar 

  42. Yanicostas C, Barbieri E, Hibi M, Brice A, Stevanin G, Soussi-Yanicostas N (2012) Requirement for zebrafish ataxin-7 in differentiation of photoreceptors and cerebellar neurons. PLoS ONE 7:e50705

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  44. Yoo SY, Pennesi ME, Weeber EJ, Xu B, Atkinson R, Chen S, Armstrong DL, Wu SM, Sweatt JD, Zoghbi HY (2003) SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 37:383–401

    Article  CAS  Google Scholar 

  45. Yvert G, Lindenberg KS, Devys D, Helmlinger D, Landwehrmeyer GB, Mandel JL (2001) SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types. Hum Mol Genet 10:1679–1692

    Article  CAS  Google Scholar 

  46. Garden GA, Libby RT, Fu YH, Kinoshita Y, Huang J, Possin DE, Smith AC, Martinez RA, Fine GC, Grote SK, Ware CB, Einum DD, Morrison RS, Ptacek LJ, Sopher BL, La Spada AR (2002) Polyglutamine-expanded ataxin-7 promotes non-cell-autonomous purkinje cell degeneration and displays proteolytic cleavage in ataxic transgenic mice. J Neurosci Official J Soc Neurosci 22:4897–4905

    Article  CAS  Google Scholar 

  47. Yvert G, Lindenberg KS, Picaud S, Landwehrmeyer GB, Sahel JA, Mandel JL (2000) Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice. Hum Mol Genet 9:2491–2506

    Article  CAS  Google Scholar 

  48. Young JE, Gouw L, Propp S, Sopher BL, Taylor J, Lin A, Hermel E, Logvinova A, Chen SF, Chen S, Bredesen DE, Truant R, Ptacek LJ, La Spada AR, Ellerby LM (2007) Proteolytic cleavage of ataxin-7 by caspase-7 modulates cellular toxicity and transcriptional dysregulation. J Biol Chem 282:30150–30160

    Article  CAS  Google Scholar 

  49. Guyenet SJ, Mookerjee SS, Lin A, Custer SK, Chen SF, Sopher BL, La Spada AR, Ellerby LM (2015) Proteolytic cleavage of ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction. Hum Mol Genet 24:3908–3917

    Article  CAS  Google Scholar 

  50. Mookerjee S, Papanikolaou T, Guyenet SJ, Sampath V, Lin A, Vitelli C, DeGiacomo F, Sopher BL, Chen SF, La Spada AR, Ellerby LM (2009) Posttranslational modification of ataxin-7 at lysine 257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment. J Neurosci Official J Soc Neurosci 29:15134–15144

    Article  CAS  Google Scholar 

  51. Takahashi J, Fujigasaki H, Zander C, El Hachimi KH, Stevanin G, Durr A, Lebre AS, Yvert G, Trottier Y, de The H, Hauw JJ, Duyckaerts C, Brice A (2002) Two populations of neuronal intranuclear inclusions in SCA7 differ in size and promyelocytic leukaemia protein content. Brain J Neurol 125:1534–1543

    Article  Google Scholar 

  52. Takahashi J, Fujigasaki H, Iwabuchi K, Bruni AC, Uchihara T, El Hachimi KH, Stevanin G, Durr A, Lebre AS, Trottier Y, de The H, Tanaka J, Hauw JJ, Duyckaerts C, Brice A (2003) PML nuclear bodies and neuronal intranuclear inclusion in polyglutamine diseases. Neurobiol Dis 13:230–237

    Article  CAS  Google Scholar 

  53. Janer A, Martin E, Muriel MP, Latouche M, Fujigasaki H, Ruberg M, Brice A, Trottier Y, Sittler A (2006) PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins. J Cell Biol 174:65–76

    Article  CAS  Google Scholar 

  54. Chort A, Alves S, Marinello M, Dufresnois B, Dornbierer JG, Tesson C, Latouche M, Baker DP, Barkats M, El Hachimi KH, Ruberg M, Janer A, Stevanin G, Brice A, Sittler A (2013) Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice. Brain J Neurol

    Google Scholar 

  55. Abou-Sleymane G, Chalmel F, Helmlinger D, Lardenois A, Thibault C, Weber C, Merienne K, Mandel JL, Poch O, Devys D, Trottier Y (2006) Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program. Hum Mol Genet 15:691–703

    Article  CAS  Google Scholar 

  56. Chou AH, Chen CY, Chen SY, Chen WJ, Chen YL, Weng YS, Wang HL (2010) Polyglutamine-expanded ataxin-7 causes cerebellar dysfunction by inducing transcriptional dysregulation. Neurochem Int 56:329–339

    Article  CAS  Google Scholar 

  57. Helmlinger D, Hardy S, Abou-Sleymane G, Eberlin A, Bowman AB, Gansmuller A, Picaud S, Zoghbi HY, Trottier Y, Tora L, Devys D (2006) Polyglutamine-expanded ataxin-7 mediates aberrant recruitment of TFTC-type complexes and chromatin decondensation leading to photoreceptor dysfunction in Spinocerebellar ataxia type 7. PLoS Biol 4:e67

    Article  Google Scholar 

  58. La Spada AR, Fu YH, Sopher BL, Libby RT, Wang X, Li LY, Einum DD, Huang J, Possin DE, Smith AC, Martinez RA, Koszdin KL, Treuting PM, Ware CB, Hurley JB, Ptacek LJ, Chen S (2001) Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 31:913–927

    Article  Google Scholar 

  59. McMahon SJ, Pray-Grant MG, Schieltz D, Yates JR 3rd, Grant PA (2005) Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity. Proc Natl Acad Sci USA 102:8478–8482

    Article  CAS  Google Scholar 

  60. Kizilyaprak C, Spehner D, Devys D, Schultz P (2011) The linker histone H1C contributes to the SCA7 nuclear phenotype. Nucleus 2:444–454

    Article  Google Scholar 

  61. Chen YC, Gatchel JR, Lewis RW, Mao CA, Grant PA, Zoghbi HY, Dent SY (2012) Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model. Hum Mol Genet 21:394–405

    Article  CAS  Google Scholar 

  62. McCullough SD, Xu X, Dent SY, Bekiranov S, Roeder RG, Grant PA (2012) Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes. Proc Natl Acad Sci USA 109:21319–21324

    Article  CAS  Google Scholar 

  63. Yang H, Liu S, He WT, Zhao J, Jiang LL, Hu HY (2015) Aggregation of polyglutamine-expanded ataxin 7 protein specifically sequesters ubiquitin-specific protease 22 and deteriorates its deubiquitinating function in the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex. J Biol Chem 290:21996–22004

    Article  CAS  Google Scholar 

  64. Lan X, Koutelou E, Schibler AC, Chen YC, Grant PA, Dent SY (2015) Poly(Q) expansions in ATXN7 affect solubility but not activity of the SAGA deubiquitinating module. Mol Cell Biol 35:1777–1787

    Article  CAS  Google Scholar 

  65. Tan JY, Vance KW, Varela MA, Sirey T, Watson LM, Curtis HJ, Marinello M, Alves S, Steinkraus BR, Cooper S, Nesterova T, Brockdorff N, Fulga TA, Brice A, Sittler A, Oliver PL, Wood MJ, Ponting CP, Marques AC (2014) Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7. Nat Struct Mol Biol 21:955–961

    Article  CAS  Google Scholar 

  66. Strom AL, Forsgren L, Holmberg M (2005) A role for both wild-type and expanded ataxin-7 in transcriptional regulation. Neurobiol Dis 20:646–655

    Article  Google Scholar 

  67. Ajayi A, Yu X, Lindberg S, Langel U, Strom AL (2012) Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible spinocerebellar ataxia type 7 (SCA7) model. BMC Neurosci 13:86

    Article  CAS  Google Scholar 

  68. Yefimova MG, Messaddeq N, Karam A, Jacquard C, Weber C, Jonet L, Wolfrum U, Jeanny JC, Trottier Y (2010) Polyglutamine toxicity induces rod photoreceptor division, morphological transformation or death in Spinocerebellar ataxia 7 mouse retina. Neurobiol Dis 40:311–324

    Article  CAS  Google Scholar 

  69. Forsgren L, Libelius R, Holmberg M, von Dobeln U, Wibom R, Heijbel J, Sandgren O, Holmgren G (1996) Muscle morphology and mitochondrial investigations of a family with autosomal dominant cerebellar ataxia and retinal degeneration mapped to chromosome 3p12–p21.1. J Neurol Sci 144:91–98

    Article  CAS  Google Scholar 

  70. Chen S, Peng GH, Wang X, Smith AC, Grote SK, Sopher BL, La Spada AR (2004) Interference of Crx-dependent transcription by ataxin-7 involves interaction between the glutamine regions and requires the ataxin-7 carboxy-terminal region for nuclear localization. Hum Mol Genet 13:53–67

    Article  CAS  Google Scholar 

  71. Marc RE, Jones BW (2003) Retinal remodeling in inherited photoreceptor degenerations. Mol Neurobiol 28:139–147

    Article  CAS  Google Scholar 

  72. Merienne K, Helmlinger D, Perkin GR, Devys D, Trottier Y (2003) Polyglutamine expansion induces a protein-damaging stress connecting heat shock protein 70 to the JNK pathway. J Biol Chem 278:16957–16967

    Article  CAS  Google Scholar 

  73. Merienne K, Friedman J, Akimoto M, Abou-Sleymane G, Weber C, Swaroop A, Trottier Y (2007) Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy. Neurobiology of disease 25:571–581

    Article  CAS  Google Scholar 

  74. Custer SK, Garden GA, Gill N, Rueb U, Libby RT, Schultz C, Guyenet SJ, Deller T, Westrum LE, Sopher BL, La Spada AR (2006) Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat Neurosci 9:1302–1311

    Article  CAS  Google Scholar 

  75. Noma S, Ohya-Shimada W, Kanai M, Ueda K, Nakamura T, Funakoshi H (2012) Overexpression of HGF attenuates the degeneration of Purkinje cells and Bergmann glia in a knockin mouse model of spinocerebellar ataxia type 7. Neurosci Res 73:115–121

    Article  CAS  Google Scholar 

  76. Furrer SA, Mohanachandran MS, Waldherr SM, Chang C, Damian VA, Sopher BL, Garden GA, La Spada AR (2011) Spinocerebellar ataxia type 7 cerebellar disease requires the coordinated action of mutant ataxin-7 in neurons and glia, and displays non-cell-autonomous Bergmann glia degeneration. J Neurosci Official J Soc Neurosci 31:16269–16278

    Article  CAS  Google Scholar 

  77. Fern RF, Matute C, Stys PK (2014) White matter injury: ischemic and nonischemic. Glia 62:1780–1789

    Article  Google Scholar 

  78. Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, Fisher PB (2008) Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem 283:13116–13123

    Article  CAS  Google Scholar 

  79. Maltecca F, Baseggio E, Consolato F, Mazza D, Podini P, Young SM Jr, Drago I, Bahr BA, Puliti A, Codazzi F, Quattrini A, Casari G (2015) Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. J Clin Invest 125:263–274

    Article  Google Scholar 

  80. Chew LJ, DeBoy CA (2015) Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology. Neuropharmacology

    Google Scholar 

  81. Murakami Y, Notomi S, Hisatomi T, Nakazawa T, Ishibashi T, Miller JW, Vavvas DG (2013) Photoreceptor cell death and rescue in retinal detachment and degenerations. Prog Retin Eye Res 37:114–140

    Article  Google Scholar 

  82. Ieraci A, Forni PE, Ponzetto C (2002) Viable hypomorphic signaling mutant of the Met receptor reveals a role for hepatocyte growth factor in postnatal cerebellar development. Proc Natl Acad Sci USA 99:15200–15205

    Article  CAS  Google Scholar 

  83. Sun W, Funakoshi H, Nakamura T (2002) Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. J Neurosci Official J Soc Neurosci 22:6537–6548

    CAS  Google Scholar 

  84. Furrer SA, Waldherr SM, Mohanachandran MS, Baughn TD, Nguyen KT, Sopher BL, Damian VA, Garden GA, La Spada AR (2013) Reduction of mutant ataxin-7 expression restores motor function and prevents cerebellar synaptic reorganization in a conditional mouse model of SCA7. Hum Mol Genet 22:890–903

    Article  CAS  Google Scholar 

  85. Ramachandran PS, Boudreau RL, Schaefer KA, La Spada AR, Davidson BL (2014) Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7. Mol Ther 22:1635–1642

    Article  CAS  Google Scholar 

  86. Greenberg J, Solomon GA, Vorster AA, Heckmann J, Bryer A (2006) Origin of the SCA7 gene mutation in South Africa: implications for molecular diagnostics. Clin Genet 70:415–417

    Article  CAS  Google Scholar 

  87. Scholefield J, Watson L, Smith D, Greenberg J, Wood MJ (2014) Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts. Eur J Hum Genet 22:1369–1375

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Nathalie Daigle for critical reading of the manuscript. YT was supported by funding from Institut National de la Santé et de la Recherche Médicale (INSERM); Centre National de la Recherche Scientifique (CNRS); University of Strasbourg; Retina-France (YT); ANR-10-LABX-0030-INRT from the French state fund through the Agence Nationale de la Recherche (ANR) under the frame programme Investissements d’Avenir ANR-10-IDEX-0002-02; the ANR-Ciliataxia N° ANR-13-BSV1-0016-01; the Fondation pour la recherche médicale (FRM DVS20131228917). AK was supported by fellowships from the fundation Connaître les Syndrômes Cérébelleux (CSC).

Conflict of Interest Statement The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, (UMR7104), Institut National de la Santé et de la Recherche Médicale (U964), Illkirch, France

    Alice Karam & Yvon Trottier

  2. Université de Strasbourg, Strasbourg, France

    Alice Karam & Yvon Trottier

Authors
  1. Alice Karam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yvon Trottier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yvon Trottier .

Editor information

Editors and Affiliations

  1. Department of Biomedical Sciences and Medicine; Centre for Biomedical Research and Algarve Biomedical Center, University of Algarve, Faro, Portugal

    Clévio Nóbrega

  2. Center for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Luís Pereira de Almeida

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Karam, A., Trottier, Y. (2018). Molecular Mechanisms and Therapeutic Strategies in Spinocerebellar Ataxia Type 7. In: Nóbrega, C., Pereira de Almeida, L. (eds) Polyglutamine Disorders. Advances in Experimental Medicine and Biology, vol 1049. Springer, Cham. https://doi.org/10.1007/978-3-319-71779-1_9

Download citation

Publish with us

Policies and ethics

Search

Navigation