Advertisement

Spinocerebellar Ataxias Caused by Polyglutamine Expansions

  • Giovanni Stevanin
  • Alexandra Dürr
  • Alexis Brice
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 516)

Abstract

Autosomal dominant cerebellar ataxias (ADCA) constitute a group of disorders, clinically and molecularly heterogeneous. They are characterized by variable degrees of cerebellar and brainstem degeneration or dysfunction. Neuronal loss variably affects the pons, the inferior olive, the basal ganglia, the cerebellum and its afferent and efferent fibers. Onset is generally during the third or fourth decade but can also occur in childhood or in the old age. Patients usually present with progressive cerebellar ataxia and associated neurological signs, such as ophthalmoplegia, pyramidal or extrapyramidal signs, deep sensory loss and dementia. Attempts to classify subtypes of ADCA were largely unsatisfactory until AE Harding distinguished three phenotypes based on clinical associated signs.1 ADCA type I is the most common subtype and variably combines cerebellar ataxia, dysarthria, ophthalmoplegia, pyramidal and extrapyramidal signs, deep sensory loss, amyotrophy and dementia. However, several other signs and symptoms may also be associated, i.e., slow eye movements, sphincter disturbances, axonal neuropathy, fasciculation and/ or swallowing difficulties. ADCA type II was first described by Froment et al2 and is characterized by the association of progressive macular degeneration with cerebellar ataxia. Finally, ADCA type III denotes a “pure”, generally late onset, cerebellar syndrome.

Keywords

Cerebellar Ataxia Spinocerebellar Ataxia Inferior Olive Spinocerebellar Ataxia Type Autosomal Dominant Cerebellar Ataxia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol 1993; 61:1–14.PubMedGoogle Scholar
  2. 2.
    Froment J, Bonnet P, Colrat A. Heredo-degenerations retinienne et spino-cerebelleuses: Variantes ophtalmoscopiques et neurologiques presentees par trois generations successives. J Med Lyon 1937; 22:153–163.Google Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Duff A, Brice A. Clinical and genetic aspects of spinocerebellar degeneration. Curr Opin Neurol 2000; 13:407–413.CrossRefGoogle Scholar
  5. 5.
    Orr HT, Chung MY, Banfi S et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genet 1993; 4:221–226.PubMedCrossRefGoogle Scholar
  6. 6.
    Pulst SM, Nechiporuk A, Nechiporuk T et al. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nature Genet 1996; 14:269–276.PubMedCrossRefGoogle Scholar
  7. 7.
    Imbert G, Saudou F, Yvert G et al. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nature Genet 1996; 14:285–291.PubMedCrossRefGoogle Scholar
  8. 8.
    Sanpei K, Takano H, Igarashi S et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nature Genet 1996; 14:277–284.PubMedCrossRefGoogle Scholar
  9. 9.
    Kawaguchi Y, Okamoto T, Taniwaki M et al. CAG expansion in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nature Genet 1994; 8:221–227.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhuchenko O Bailey J, Bonnen P et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nature Genet 1997; 15:62–69.PubMedCrossRefGoogle Scholar
  11. 11.
    David G, Abbas N, Stevanin G et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nature Genet 1997; 17:65–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Koide R, Kobayashi S, Shimohata T 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; 8:2047–2053.PubMedCrossRefGoogle Scholar
  13. 13.
    Koob MD, Moseley ML, Schut LJ et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8), Nature Genet 1999; 21:379–384.PubMedCrossRefGoogle Scholar
  14. 14.
    Matsuura T, Yamagata T, Burgess DL et al. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 2000; 26:191–194.PubMedCrossRefGoogle Scholar
  15. 15.
    Holmes SE, O’Heam EE, McInnis MG et al. Expansion of a novel CAG trinucleotide repeat in the 5’ region of PPP2R2B is associated with SCAl2. Nat Genet 1999; 23:391–392.PubMedCrossRefGoogle Scholar
  16. 16.
    Vincent JB, Yuan QP, Schalling M et al. Long repeat tracts at SCA8 in major psychosis. Am J Med Genet 2000; 96:873–876.PubMedCrossRefGoogle Scholar
  17. 17.
    Worth PF, Houlden H, Giunti P et al. Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. Nat Genet 2000; 24:214–215.PubMedCrossRefGoogle Scholar
  18. 18.
    Stevanin G, Herman A, Durr A et al. Are (CTG)n expansions at the SCA8 locus rare polymorphisms? Nat Genet 2000; 24:213.PubMedCrossRefGoogle Scholar
  19. 19.
    Giunti P, Stevanin G, Worth P et al. Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation. Am J Hum Genet 1999; 64:1594–1603.PubMedCrossRefGoogle Scholar
  20. 20.
    Devos D, Schraen-Maschke S, Vuillaume I et al. Clinical features and genetic analysis of a new form of spinocerebellar ataxia. Neurology 2001; 56:234–238.PubMedCrossRefGoogle Scholar
  21. 21.
    Zoghbi HY, Ott HT. Glutamine repeats and neurodegeneration. Ann Rev Neurosci 2000; 23:217–247.PubMedCrossRefGoogle Scholar
  22. 22.
    Jodice C, Mantuano E, Veneziano L et al. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNAIA gene on chromosome 19p. Hum Mol Genet 1997; 6:1973–1978.PubMedCrossRefGoogle Scholar
  23. 23.
    van Schaik IN, Jobsis GJ, Vermeulen M et al. Machado-Joseph disease presenting as severe asymmetric proximal neuropathy. J Neurol Neurosurg Psychiatry 1997; 63:534–536.PubMedCrossRefGoogle Scholar
  24. 24.
    Pratt RTC. The Genetics of Neurological Disorders. London: Oxford University Press, 1967.Google Scholar
  25. 25.
    Hirayama K, Takayanagi T, Nakamura R et al. Spinocerebellar degenerations in Japan: A nationwide epidemiological and clinical study. Acta Neurol Scand 1994; 153 (Suppl.):1–22.CrossRefGoogle Scholar
  26. 26.
    Leone M, Bottacchi E, D’Alessandro G et al. Hereditary ataxias and paraplegias in Valle d’Aosta, Italy: a study of prevalence and disability. Acta Neurol Scand 1995; 91:183–187.PubMedCrossRefGoogle Scholar
  27. 27.
    Sridharan R, Radhakrishnan K, Ashok PP et al. Prevalence and pattern of spinocerebellar degenerations in northeastern Libya. Brain 1985; 108:831–483.PubMedCrossRefGoogle Scholar
  28. 28.
    Orozco G, Estrada R, Perry TL et al. Dominantly inherited olivopontocerebellar atrophy from eastern Cuba. Clinical, neuropathological, and biochemical findings. J Neurol Sci 1989; 93:37–50.PubMedCrossRefGoogle Scholar
  29. 29.
    Sequeiros J and Coutinho P. Epidemiology and clinical aspects of Machado-Joseph disease. Adv Neurol 1993; 61:139–153.PubMedGoogle Scholar
  30. 30.
    Wakisaka A, Sasaki H, Takada A et al. Spinocerebellar ataxia I (SCAT) in the Japanese in Hokkaido may derive from a single common ancestry. J Med Genet 1995; 32:590–592.PubMedCrossRefGoogle Scholar
  31. 31.
    Didierjean 0, Cancel G, Stevanin G et al. Linkage disequilibrium at the SCA2 locus. J Med Genet 1999; 36:415–417.PubMedGoogle Scholar
  32. 32.
    Saleem Q, Choudhry S, Mulcetji M et al. Molecular analysis of autosomal dominant hereditary ataxias in the Indian population: high frequency of SCA2 and evidence for a common founder mutation. Hum Genet 2000; 106:179–187.PubMedCrossRefGoogle Scholar
  33. 33.
    Stevanin G, Cancel G, Didierjean 0 et al. Linkage disequilibrium at the Machado-Joseph disease/Spinal cerebellar ataxia 3 locus: evidence for a common founder effect in French and Portuguese-Brazilian families as well as a second ancestral Portuguese-Azorean mutation. Am J Hum Genet 1995; 57:1247–1250.PubMedGoogle Scholar
  34. 34.
    Takiyama Y, Igarashi 5, Rogaeva EA et al. Evidence for inter-generational instability in the CAG repeat in the MJD I gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease. Hum Mol Genet 1995; 4:1137–1146.PubMedCrossRefGoogle Scholar
  35. 35.
    Gaspar C, Lopes-Cendes I, DeStefano AL et al. Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins. Hum Genet 1996; 98:620–624.PubMedCrossRefGoogle Scholar
  36. 36.
    Endo K, Sasaki H, Wakisaka A et al. Strong linkage disequilibrium and haplotype analysis in Japanese pedigrees with Machado-Joseph disease. Am J Med Genet 1996; 67:437–444.PubMedCrossRefGoogle Scholar
  37. 37.
    Stevanin G, Lebre AS, Mathieux C et al. Linkage disequilibrium between the spinocerebellar ataxia 3/Machado-Joseph disease mutation and two intragenic polymorphisms, one of which, X359Y, affects the stop codon. Am J Hum Genet 1997; 60:1548–1552.PubMedCrossRefGoogle Scholar
  38. 38.
    Dichgans M, Schols L, Herzog J et al. Spinocerebellar ataxia type 6: Evidence for a strong founder effect among German families. Neurology 1999; 52:849–851.PubMedCrossRefGoogle Scholar
  39. 39.
    Jonasson J, Juvonen V, Sistonen P et al. Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia. Eur J Hum Genet 2000; 8:918–922.PubMedCrossRefGoogle Scholar
  40. 40.
    Stevanin G, David G, Durr A et al. Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by linkage disequilibrium studies with closely flanking markers, including an intragenic polymorphism (G3145TG/A3145TG). Eur J Hum Genet 1999; 7:889–896.PubMedCrossRefGoogle Scholar
  41. 41.
    Mayo CD, Hernandez CJ, Cantarero DS et al. Distribution of dominant hereditary ataxias and Friedreich’s ataxia in the Spanish population. Med Clin (Barc) 2000; 115:121–125.Google Scholar
  42. 42.
    Filla A, Mariotti C, Caruso G et al. Relative frequencies of CAG expansions in spinocerebellar ataxia and dentatorubropallidoluysian atrophy in 116 Italian families. Eur Neurol 2000; 44:31–36.PubMedCrossRefGoogle Scholar
  43. 43.
    Silveira I, Coutinho P, Maciel P et al. Analysis of SCA1, DRPLA, MJD, SCA2, and SCA6 CAG repeats in 48 Portuguese ataxia families. Am J Med Genet 1998; 81:134–138.PubMedCrossRefGoogle Scholar
  44. 44.
    Watanabe H, Tanaka F, Matsumoto M et al. Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6. Clin Genet 1998; 53:13–19.PubMedCrossRefGoogle Scholar
  45. 45.
    Matsumura R, Futamura N, Fujimoto Y et al. Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology 1997; 49:1238–1243.PubMedCrossRefGoogle Scholar
  46. 46.
    Pujana MA, Corral J, Gratacos M et al. Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases. The Ataxia Study Group. Hum Genet 1999; 104:516–522.PubMedCrossRefGoogle Scholar
  47. 47.
    Basu P, Chattopadhyay B, Gangopadhaya PK et al. Analysis of CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7 and DRPLA loci in spinocerebellar ataxia patients and distribution of CAG repeats at the SCA1, SCA2 and SCA6 loci in nine ethnic populations of eastern India. Hum Genet 2000; 106:597–604.PubMedCrossRefGoogle Scholar
  48. 48.
    Gaspar C, Lopes-Cendes I, Hayes S et al. Ancestral origins of the Machado-Joseph disease mutation: A worldwide haplotype study. Am J Hum Genet 2001; 68:523–528.PubMedCrossRefGoogle Scholar
  49. 49.
    Kang S, Jaworski A, Ohshima K et al. Expansion and deletion of CTG repeats from human disease genes are determined by the direction of replication in E.coli. Nature Genet 1995; 10:213–218.PubMedCrossRefGoogle Scholar
  50. 50.
    Wells RD, Warren ST. Wells RD, Warren ST, eds. Genetic Instabilities and Hereditary Neurological Diseases. San Diego: Academic press, 1998.Google Scholar
  51. 51.
    Kennedy L and Shelboume PF. Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington’s disease? Hum Mol Genet 2000; 9:2539–2544.PubMedCrossRefGoogle Scholar
  52. 52.
    Ranen NG, Stine OC, Abbott MH et al. Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet 1995; 57:593–602.PubMedGoogle Scholar
  53. 53.
    David G, Diirr A, Stevanin G et al. Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). Hum Mol Genet 1998; 7:165–170.PubMedCrossRefGoogle Scholar
  54. 54.
    Igarashi S, Takiyama Y, Cancel G et al. Intergenerational instability of the CAG repeat of the Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome: Implications for the molecular mechanisms of the instability of the CAG repeat. Hum Mol Genet 1996; 5:923–932.PubMedCrossRefGoogle Scholar
  55. 55.
    Takiyama Y, Sakoe K, Soutome M et al. Single sperm analysis of the CAG repeats in the gene for Machado- Joseph disease (MJD1): Evidence for nonMendelian transmission of the MJD1 gene and for the effect of the intragenic CGG/GGG polymorphism on theintergenerational instability. Hum Mol Genet 1997; 6:1063–1068.PubMedCrossRefGoogle Scholar
  56. 56.
    Chong SS, McCall AE, Cota J et al. Gametic and somatic tissue-specific heterogeneity of the expanded SCA1 CAG repeat in spinocerebellar ataxia type 1. Nature Genet 1995; 10:344–350.PubMedCrossRefGoogle Scholar
  57. 57.
    Cancel G, Abbas N, Stevanin G et al. Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus. Am J Hum Genet 1995; 57:809–816.PubMedGoogle Scholar
  58. 58.
    Monckton DG, Cayuela ML, Gould FK et al. Very large (CAG)(n) DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males. Hum Mol Genet 1999; 8:2473–2478.PubMedCrossRefGoogle Scholar
  59. 59.
    Gouw LG, Castaneda MA, McKenna CK et al. Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission. Hum Mol Genet 1998; 7:525–532.PubMedCrossRefGoogle Scholar
  60. 60.
    Grewal RP, Cancel G, Leeflang EP et al. French Machado-Joseph disease patients do not exhibit gametic segregation distortion: A sperm typing analysis. Hum Mol Genet 1999; 8:1779–1784.PubMedCrossRefGoogle Scholar
  61. 61.
    Chung MY, Ranum LP, Duvick LA et al. Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nature Genet 1993; 5:254–258.PubMedCrossRefGoogle Scholar
  62. 62.
    Quan F, Janas J, and Popovich BW. A novel CAG repeat configuration in the SCA I gene: Implications for the molecular diagnostics of spinocerebellar ataxia type 1. Hum Mol Genet 1995; 4:2411–2413.PubMedCrossRefGoogle Scholar
  63. 63.
    Cancel G, Dürr A, Didierjean 0 et al. Molecular and clinical correlations in spinocerebellar ataxia 2: A study of 32 families. Hum Mol Genet 1997; 6:709–715.PubMedCrossRefGoogle Scholar
  64. 64.
    Stevanin G, Duff A, David G et al. Clinical and molecular features of spinocerebellar ataxia type 6. Neurology 1997; 49:1243–1246.PubMedCrossRefGoogle Scholar
  65. 65.
    Babovic-Vuksanovic D, Snow K, Patterson MC et al. Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 1998; 79:383–387.PubMedCrossRefGoogle Scholar
  66. 66.
    Johansson J, Forsgren L, Sandgren 0 et al. Expanded CAG repeat in Swedish Spinocerebellar ataxia type 7 (SCA7) patients: Effect of CAG repeat length on the clinical manifestation. Hum Mol Genet 1998; 7:171–176.PubMedCrossRefGoogle Scholar
  67. 67.
    Benton CS, de Silva R, Rutledge SL et al. Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 1998; 51:1081–1086.PubMedCrossRefGoogle Scholar
  68. 68.
    Stevanin G, Giunti P, Belal G et al. De novo expansion of intermediate alleles in spinocerebellar ataxia 7. Hum Mol Genet 1998; 7:1809–1813.PubMedCrossRefGoogle Scholar
  69. 69.
    Takano H, Cancel G, Ikeuchi T et al. Close associations between prevalences of dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations. Am J Hum Genet 1998; 63:1060–1066.PubMedCrossRefGoogle Scholar
  70. 70.
    Yanagisawa H, Fujii K, Nagafuchi S et al. A unique origin and multistep process for the generation of expanded DRPLA triplet repeats. Hum Mol Genet 1996; 5:373–379.PubMedCrossRefGoogle Scholar
  71. 71.
    Goldberg YP, McMurray CT, Zeisler J et al. Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population. Hum Mol Genet 1995; 4:1911–1918.PubMedCrossRefGoogle Scholar
  72. 72.
    Ranum LP, Chung MY, Banfi S 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; 55:244–252.PubMedGoogle Scholar
  73. 73.
    DeStefano AL, Cupples LA, Maciel P et al. A familial factor independent of CAG repeat length influences age at onset of Machado-Joseph disease. Am J Hum Genet 1996; 59:119–127.PubMedGoogle Scholar
  74. 74.
    Hayes S, Turecki G, Brisebois K et al. CAG repeat length in RAII is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2). Hum Mol Genet 2000; 9:1753–1758.PubMedCrossRefGoogle Scholar
  75. 75.
    Kawakami H, Maruyama H, Nakamura S et al. Unique features of the CAG repeats in Machado-Joseph disease. Nature Genet 1995; 9:344–345.PubMedCrossRefGoogle Scholar
  76. 76.
    Lerer I, Merims D, Abeliovich D et al. Machado-Joseph disease: Correlation between the clinical features, the CAG repeat length and homozygosity for the mutation. Eur J Hum Genet 1996; 4:3–7.PubMedGoogle Scholar
  77. 77.
    Sobue G, Doyu M, Nakao N et al. Homozygosity for Machado-Joseph disease gene enhances phenotypic severity. J Neurol Neurosurg Psychiatry 1996; 60:354–356.PubMedCrossRefGoogle Scholar
  78. 78.
    Geschwind DH, Perlman S, Figueroa KP et al. Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations. Neurology 1997; 49:1247–1251.PubMedCrossRefGoogle Scholar
  79. 79.
    Ikeuchi T, Takano H, Koide R et al. Spinocerebellar ataxia type 6: CAG repeat expansion in alphal A voltage-dependent calcium channel gene and clinical variations in Japanese population. Ann Neurol 1997; 42:879–884.PubMedCrossRefGoogle Scholar
  80. 80.
    Abe T, Tsuda T, Yoshida M et al. Macular degeneration associated with aberrant expansion of trinucleotide repeat of the SCA7 gene in 2 Japanese families. Arch Ophthalmol 2000; 118:1415–1421.PubMedCrossRefGoogle Scholar
  81. 81.
    Kouno R, Kawata A, Yoshida H et al. A family of SCAT with pigmentary macular dystrophy. Rinsho Shinkeigaku 1999; 39:649–652.PubMedGoogle Scholar
  82. 82.
    Biirk K, Abele M, Fetter M et al. Autosomal dominant cerebellar ataxia type I: Clinical features and MRI in families with SCA I, SCA2 and SCA3. Brain 1996; 119:1497–1505.CrossRefGoogle Scholar
  83. 83.
    Burk K, Fetter M, Skalej M et al. Saccade velocity in idiopathic and autosomal dominant cerebellar ataxia. J Neurol Neurosurg Psychiatry 1997; 62:662–664.PubMedCrossRefGoogle Scholar
  84. 84.
    Schols L, Amoiridis G, Buttner T et al. Autosomal dominant cerebellar ataxia: Phenotypic differences in genetically defined subtypes? Ann Neurol 1997; 42:924–932.PubMedCrossRefGoogle Scholar
  85. 85.
    Wadia N, Pang J, Desai J et al. A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis. Brain 1998; 121:2341–2355.PubMedCrossRefGoogle Scholar
  86. 86.
    Burk K, Globas C, Bosch S et al. Cognitive deficits in spinocerebellar ataxia 2. Brain 1999; 122:769–777.PubMedCrossRefGoogle Scholar
  87. 87.
    Filla A, De Michele G, Santoro L et al. Spinocerebellar ataxia type 2 in southern Italy: A clinical and molecular study of 30 families. J Neurol 1999; 246:467–471.PubMedCrossRefGoogle Scholar
  88. 88.
    Matilla T, McCall A, Subramony SH et al. Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease. Ann Neurol 1995; 38:68–72.PubMedCrossRefGoogle Scholar
  89. 89.
    Stevanin G, Le Guern E, Ravise N et al. A third locus for autosomal dominant cerebellar ataxia type I maps to chromosome 14q24.3-qter: Evidence for the existence of a fourth locus. Am J Hum Genet 1994; 54:11–20.PubMedGoogle Scholar
  90. 90.
    Durr A, Stevanin G, Cancel G et al. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular and neuropathological features. Ann Neurol 1996; 39:490–499.PubMedCrossRefGoogle Scholar
  91. 91.
    Schols L, Amoiridis G, Epplen JT et al. Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation. J Neurol Neurosurg Psychiatry 1996; 61:466–470.PubMedCrossRefGoogle Scholar
  92. 92.
    Schols L, Vieira-Saecker AM, Schols S et al. Trinucleotide expansion within the MJDI gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients. Hum Mol Genet 1995;4:1001–1005.PubMedCrossRefGoogle Scholar
  93. 93.
    Ranum LP, Schut LJ, Lundgren JK et al. Spinocerebellar ataxia type 5 in a family descended from the grandparents of President Lincoln maps to chromosome 11. Nature Genet 1994; 8:280–284.PubMedCrossRefGoogle Scholar
  94. 94.
    Stevanin G, Herman A, Brice A et al. Clinical and MRI findings in spinocerebellar ataxia type 5. Neurology 1999; 53:1355–1357.PubMedCrossRefGoogle Scholar
  95. 95.
    Nakamura K, Jeong SY, Ichikawa Y et al. SCA15, a novel autosomal dominant cerebellar ataxia caused by the expanded polyglutamine in TATA-binding protein identified with 1C2 antibody immunoscreening. Am J Hum Genet 2000; 67 (Suppl 2):2185.Google Scholar
  96. 96.
    Rivaud-Pechoux S, Durr A, Gaymard B et al. Eye movement abnormalities correlate with genotype in autosomal dominant cerebellar ataxia type I. Ann Neurol 1998; 43:297–302.PubMedCrossRefGoogle Scholar
  97. 97.
    Burk K, Fetter M, Abele M et al. Autosomal dominant cerebellar ataxia type I: Oculomotor abnormalities in families with SCAT, SCA2, and SCA3. J Neurol 1999; 246:789–797.PubMedCrossRefGoogle Scholar
  98. 98.
    Gomez CM, Thompson RM, Gammack JT et al. Spinocerebellar ataxia type 6: Gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann Neurol 1997; 42:933–950.PubMedCrossRefGoogle Scholar
  99. 99.
    Schols L, Kruger R, Amoiridis G et al. Spinocerebellar ataxia type 6: Genotype and phenotype in German kindreds. J Neurol Neurosurg Psychiatry 1998; 64:67–73.PubMedCrossRefGoogle Scholar
  100. 100.
    Sugawara M, Toyoshima I, Wada C et al. Pontine atrophy in spinocerebellar ataxia type 6. Eur Neurol 2000; 43:17–22.PubMedCrossRefGoogle Scholar
  101. 101.
    Iwabuchi K, Tsuchiya K, Uchihara T et al. Autosomal dominant spinocerebellar degenerations. Clinical, pathological, and genetic correlations. Rev Neurol (Paris) 1999; 155:255–270.Google Scholar
  102. 102.
    Robitaille Y, Schut L, and Kish SJ. Structural and immunocytochemical features of olivoponto-cerebellar atrophy caused by the spinocerebellar ataxia type I (SCA-1) mutation define a unique phenotype. Acta Neuropathol (Berl) 1995; 90:572–581.CrossRefGoogle Scholar
  103. 103.
    Gilman S, Sima AA, Junck L et al. Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. Ann Neurol 1996; 39:241–255.PubMedCrossRefGoogle Scholar
  104. 104.
    Durr A, Smadja D, Cancel G et al. Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies): Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. Brain 1995; 118:1573–1581.PubMedCrossRefGoogle Scholar
  105. 105.
    Jodice C, Malaspina P, Persichetti F et al. Effect of trinucleotide repeat length and parental sex on phenotypic variation in spinocerebellar ataxia I. Am J Hum Genet 1994; 54:959–965.PubMedGoogle Scholar
  106. 106.
    Klockgether T, Kramer B, Ludtke R et al. Repeat length and disease progression in spinocerebellar ataxia type 3. Lancet 1996; 348:830–830.PubMedCrossRefGoogle Scholar
  107. 107.
    Tuite PI, Rogaeva EA, St George-Hyslop PH et al. Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: Confirmation of 14q CAG expansion. Ann Neurol 1995; 38:684–687.PubMedCrossRefGoogle Scholar
  108. 108.
    Martin J, Van Regemorter N, Del-Favero J et al. Spinocerebellar ataxia type 7 (SCA7)-- Correlations between phenotype and genotype in one large Belgian family. J Neurol Sci 1999; 168:37–46.PubMedCrossRefGoogle Scholar
  109. 109.
    Durr A, Chneiweiss H, Khati C et al. Phenotypic variability in autosomal dominant cerebellar ataxia type I is unrelated to genetic heterogeneity. Brain 1993; 116:1497–1508.PubMedCrossRefGoogle Scholar
  110. 110.
    Spadaro M, Giunti P, Lulli P et al. HLA-linked spinocerebellar ataxia: A clinical and genetic study of large Italian kindreds. Acta Neurol Scand 1992; 85:257–65.PubMedCrossRefGoogle Scholar
  111. 111.
    Mushegian AR, Vishnivetskiy SA, Gurevich VV. Conserved phosphoprotein interaction motif is functionally interchangeable between ataxin-7 and arrestins. Biochemistry 2000; 39:6809–6813.PubMedCrossRefGoogle Scholar
  112. 112.
    Neuwald AF, Koonin EV. Ataxin-2, global regulators of bacterial gene expression, and spliceosomal snRNP proteins share a conserved domain. J Mol Med 1998; 76:3–5.PubMedCrossRefGoogle Scholar
  113. 113.
    Koyano S, Uchihara T, Fujigasaki H et al. Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: Triple-labeling immunofluorescent study. Neurosci Lett 1999; 273:117–120.PubMedCrossRefGoogle Scholar
  114. 114.
    Lindenberg KS, Yvert G, Muller K et al. Expression analysis of ataxin-7 mRNA and protein in human brain: evidence for a widespread distribution and focal protein accumulation. Brain Pathol 2000; 10:385–394.PubMedCrossRefGoogle Scholar
  115. 115.
    Servadio A, Koshy B, Armstrong D et al. Expression analysis of the ataxin-1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature Genet 1995; 10:94–98.PubMedCrossRefGoogle Scholar
  116. 116.
    Yue S, Serra HG, Zoghbi HY et al. The spinocerebellar ataxia type I 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.PubMedCrossRefGoogle Scholar
  117. 117.
    Huynh DP, Del Bigio MR, Ho DH et al. Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer’s disease and spinocerebellar ataxia 2. Ann Neurol 1999; 45:232–241.PubMedCrossRefGoogle Scholar
  118. 118.
    Paulson HL, Das SS, Crino PB et al. Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol 1997; 41:453–462.PubMedCrossRefGoogle Scholar
  119. 119.
    Schmidt T, Landwehrmeyer GB, Schmitt I et al. An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 1998; 8:669–679.PubMedCrossRefGoogle Scholar
  120. 120.
    Cancel G, Duyckaerts C, Holmberg M et al. Distribution of ataxin-7 in normal human brain and retina. Brain 2000; 123:2519–2530.PubMedCrossRefGoogle Scholar
  121. 121.
    Kaytor MD, Duvick LA, Skinner PJ et al. Nuclear localization of the spinocerebellar ataxia type 7 protein, ataxin-7. Hum Mol Genet 1999; 8:1657–1664.PubMedCrossRefGoogle Scholar
  122. 122.
    Heintz N and Zoghbi HY. Insights from mouse models into the molecular basis of neurodegeneration. Annu Rev Physiol 2000; 62:779–802.PubMedCrossRefGoogle Scholar
  123. 123.
    Yvert G, Lindenberg KS, Picaud S et al. Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCAT transgenic mice. Hum Mol Genet 2000; 9:2491–2506.PubMedCrossRefGoogle Scholar
  124. 124.
    Lin CH, Tallaksen-Greene S, Chien WM et al. Neurological abnormalities in a knock-in mouse model of Huntington’s disease. Hum Mol Genet 2001; 10:137–144.PubMedCrossRefGoogle Scholar
  125. 125.
    Trottier Y, Lutz Y, Stevanin G et al. Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 1995; 378:403–406.PubMedCrossRefGoogle Scholar
  126. 126.
    Stevanin G, Trottier Y, Cancel G et al. Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias. Hum Mol Genet 1996; 5:1887–1892.PubMedCrossRefGoogle Scholar
  127. 127.
    Perez MK, Paulson HL, and Pittman RN. Ataxin-3 with an altered conformation that exposes the polyglutamine domain is associated with the nuclear matrix. Hum Mol Genet 1999; 8:2377–2385.PubMedCrossRefGoogle Scholar
  128. 128.
    Lunkes A and Mandel J-L. Polyglutamines, nuclear inclusions and neurodegeneration. Nature Med 1997; 3:1201–1202.PubMedCrossRefGoogle Scholar
  129. 129.
    Ishikawa K, Fujigasaki H, Saegusa H et al. Abundant expression and cytoplasmic aggregations of [alpha]] A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. Hum Mol Genet 1999; 8:1185–1193.PubMedCrossRefGoogle Scholar
  130. 130.
    Huynh DP, Figueroa K, Hoang N et al. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet 2000; 26:44–50.PubMedCrossRefGoogle Scholar
  131. 131.
    Koyano S, Uchihara T, Fujigasaki H et al. Neuronal intranuclear inclusions in spinocerebellar ataxia type 2. Ann Neurol 2000; 47:550.PubMedCrossRefGoogle Scholar
  132. 132.
    Monoi H, Futaki S, Kugimiya S et al. Poly-L-glutamine forms cation channels: Relevance to the pathogenesis of the polyglutamine diseases. Biophys J 2000; 78:2892–2899.PubMedCrossRefGoogle Scholar
  133. 133.
    Hirakura Y, Azimov R, Azimova R et al. Polyglutamine-induced ion channels: A possible mechanism for the neurotoxicity of Huntington and other CAG repeat diseases. J Neurosci Res 2000; 60:490–494.PubMedCrossRefGoogle Scholar
  134. 134.
    Green H. Human genetic diseases due to codon reiteration: Relationship to an evolutionary mechanism. Cell 1993; 74:955–956.Google Scholar
  135. 135.
    Kahlem P, Terre C, Green H et al. Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: Relevance to diseases of the nervous system. Proc Natl Acad Sci U S A 1996; 93:14580–14585.PubMedCrossRefGoogle Scholar
  136. 136.
    Perutz MF, Johnson T, Suzuki M et al. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc Natl Acad Sci USA 1994; 91:5355–5358.PubMedCrossRefGoogle Scholar
  137. 137.
    Wanker EE. Protein aggregation and pathogenesis of Huntington’s disease: Mechanisms and correlations. Biol Chem 2000; 381:937–942.PubMedCrossRefGoogle Scholar
  138. 138.
    Hollenbach B, Scherzinger E, Schweiger K et al. Aggregation of truncated GST-HD exon 1 fusion proteins containing normal range and expanded glutamine repeats. Philos Trans R Soc Lond B Biol Sci 1999; 354:991–994.PubMedCrossRefGoogle Scholar
  139. 139.
    Scherzinger E, Sittler A, Schweiger K et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington’s disease pathology. Proc Natl Acad Sci U S A 1999; 96:4604–4609.PubMedCrossRefGoogle Scholar
  140. 140.
    Kahlem P, Green H, and Djian P. Transglutaminase action imitates Huntington’s disease: Selective polymerization of Huntingtin containing expanded polyglutamine. Mol Cell 1998; 1:595–601.PubMedCrossRefGoogle Scholar
  141. 141.
    Igarashi S, Koide R, Shimohata T et al. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nature Genet 1998; 18:111–117.PubMedCrossRefGoogle Scholar
  142. 142.
    Saudou F, Finkbeiner S, Devys D et al. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998; 95:55–66.PubMedCrossRefGoogle Scholar
  143. 143.
    Brais B, Bouchard JP, Xie YG et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nature Genet 1998; 18:164–167.PubMedCrossRefGoogle Scholar
  144. 144.
    Perutz MF. Glutamine repeats and inherited neurodegenerative diseases: molecular aspects. Curr Opin Struct Biol 1996; 6:848–858.PubMedCrossRefGoogle Scholar
  145. 145.
    Gaspar C, Jannatipour M, Dion P et al. CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Hum Mol Genet 2000; 9:1957–1966.PubMedCrossRefGoogle Scholar
  146. 146.
    Paulson HL, Perez MK, Trottier Y et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 1997; 19:333–344.PubMedCrossRefGoogle Scholar
  147. 147.
    Martindale D, Hackam A, Wieczorek A et al. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nature Genet 1998; 18:150–154.PubMedCrossRefGoogle Scholar
  148. 148.
    Welch WJ, Gambetti P. Chaperoning brain diseases. Nature 1998; 392:23–24.PubMedCrossRefGoogle Scholar
  149. 149.
    Wellington CL, Hayden MR. Caspases and neurodegeneration: On the cutting edge of new therapeutic approaches. Clin Genet 2000; 57:1–10.PubMedCrossRefGoogle Scholar
  150. 150.
    Wellington CL, Ellerby LM, Hackam AS et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 1998; 273:9158–9167.PubMedCrossRefGoogle Scholar
  151. 151.
    Ikeda H, Yamaguchi M, Sugai S et al. Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nature Genet 1996; 13:196–202.PubMedCrossRefGoogle Scholar
  152. 152.
    Ellerby LM, Andrusiak RL, Wellington CL et al. Cleavage of atrophin-I at caspase site aspartic acid 109 modulates cytotoxicity. J Biol Chem 1999; 274:8730–8736.PubMedCrossRefGoogle Scholar
  153. 153.
    Hackam AS, Singaraja R, Zhang T et al. In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington’s disease. Hum Mol Genet 1999; 8:25–33.PubMedCrossRefGoogle Scholar
  154. 154.
    Cooper JK, Schilling G, Peters MF et al. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet 1998; 7:783–790.PubMedCrossRefGoogle Scholar
  155. 155.
    Merry DE, Kobayashi Y, Bailey CK et al. Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum Mol Genet 1998; 7:693–701.PubMedCrossRefGoogle Scholar
  156. 156.
    Ona VO, Li M, Vonsattel JP et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature 1999; 399:263–267.PubMedCrossRefGoogle Scholar
  157. 157.
    Bailey CK, McCampbell A, Madura K et al. Biochemical analysis of high molecular weight protein aggregates containing expanded polyglutamine repeat androgen receptor. Am J Hum Genet 1998; 63 (Suppl):A8.Google Scholar
  158. 158.
    Cummings CJ, Mancini MA, Antalffy B et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCAT. Nature Genet 1998; 19:148–154.PubMedCrossRefGoogle Scholar
  159. 159.
    Chai Y, Koppenhafer SL, Shoesmith SJ et al. Evidence for proteasome involvement in polyglutamine disease: Localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum Mol Genet 1999; 8:673–682.PubMedCrossRefGoogle Scholar
  160. 160.
    Stenoien DL, Cummings CJ, Adams HP et al. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-I, and are suppressed by the HDJ-2 chaperone. Hum Mol Genet 1999; 8:731–741.PubMedCrossRefGoogle Scholar
  161. 161.
    Wyttenbach A, Carmichael J, Swartz J et al. Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington’s disease. Proc Nati Acad Sci USA 2000; 97:2898–2903.CrossRefGoogle Scholar
  162. 162.
    Chai Y, Koppenhafer SL, Bonini NM et al. Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J Neurosci 1999; 19:10338–10347.PubMedGoogle Scholar
  163. 163.
    Warrick JM, Chan HY, Gray-Board GL et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 1999; 23:425–428.PubMedCrossRefGoogle Scholar
  164. 164.
    Muchowski Pi, Schaffar G, Sittler A et al. Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Nati Acad Sci USA 2000; 97:7841–7846.CrossRefGoogle Scholar
  165. 165.
    Mangiarini L, Sathasivam K, Seller M et al. Exon I of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 1996; 87:493–506.PubMedCrossRefGoogle Scholar
  166. 166.
    Davies SW, Turmaine M, Cozens BA et al. Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997; 90:537–548.PubMedCrossRefGoogle Scholar
  167. 167.
    Warrick JM, Paulson HL, Gray-Board GL et al. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 1998; 93:939–949.PubMedCrossRefGoogle Scholar
  168. 168.
    Holmberg M, Duyckaerts C, Durr A et al. Spinocerebellar ataxia type 7 (SCA7): A neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 1998; 7:913–918.PubMedCrossRefGoogle Scholar
  169. 169.
    Sathasivam K, Hobbs C, Turmaine M et al. Formation of polyglutamine inclusions in nonCNS tissue. Hum Mol Genet 1999; 8:813–822.PubMedCrossRefGoogle Scholar
  170. 170.
    Fain JN, Del Mar NA, Meade CA et al. Abnormalities in the functioning of adipocytes from R6/2 mice that are transgenic for the Huntington’s disease mutation. Hum Mol Genet 2001; 10:145–152.PubMedCrossRefGoogle Scholar
  171. 171.
    Klement IA, Skinner PJ, Kaytor MD et al. Ataxin-1 nuclear localization and aggregation: Role in polyglutamine-induced disease in SCAT transgenic mice. Cell 1998; 95:41–53.PubMedCrossRefGoogle Scholar
  172. 172.
    Sisodia SS. Nuclear inclusions in glutamine repeat disorders: Are they pernicious, coincidental, or beneficial? Cell 1998; 95:1–4.PubMedGoogle Scholar
  173. 173.
    Wood JD, Nucifora FC, Duan K 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; 150:939–948.PubMedCrossRefGoogle Scholar
  174. 174.
    Skinner PJ, Koshy BT, Cummings CI et al. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 1997; 389:971–974.PubMedCrossRefGoogle Scholar
  175. 175.
    Yamada M, Wood JD, Shimohata T et al. Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubralpallidoluysian atrophy. Ann Neurol 2001; 49:14–23.PubMedCrossRefGoogle Scholar
  176. 176.
    Perez MK, Paulson HL, Pendse SJ et al. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 1998; 143:1457–1470.PubMedCrossRefGoogle Scholar
  177. 177.
    Matilla A, Koshy BT, Cummings CJ et al. The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-l. Nature 1997; 389:974–978.PubMedCrossRefGoogle Scholar
  178. 178.
    Steffan JS, Kazantsev A, Spasic-Boskovic 0 et al. The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci USA 2000; 97:6763–6768.PubMedCrossRefGoogle Scholar
  179. 179.
    Shimohata T, Nakajima T, Yamada M et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 2000; 26:29–36.PubMedCrossRefGoogle Scholar
  180. 180.
    McCampbell A, Taylor JP, Taye AA et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 2000; 9:2197–2202.PubMedCrossRefGoogle Scholar
  181. 181.
    Lin X, Antalffy B, Kang D et al. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCAT. Nat Neurosci 2000; 3:157–163.PubMedCrossRefGoogle Scholar
  182. 182.
    Vig PJ, Subramony SH, Qin Z et al. Relationship between ataxin-I nuclear inclusions and Purkinje cell specific proteins in SCA-1 transgenic mice. J Neurol Sci 2000; 174:100–110.PubMedCrossRefGoogle Scholar
  183. 183.
    Iannicola C, Moreno S, Oliverio S et al. Early alterations in gene expression and cell morphology in a mouse model of Huntington’s disease. J Neurochem 2000; 75:830–839.PubMedCrossRefGoogle Scholar
  184. 184.
    Li SH, Cheng AL, Li H et al. Cellular defects and altered gene expression in PC12 cells stably expressing mutant huntingtin. J Neurosci 1999; 19:5159–5172.PubMedGoogle Scholar
  185. 185.
    Tabrizi SJ, Cleeter MW, Xuereb J et al. Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann Neurol 1999; 45:25–32.PubMedCrossRefGoogle Scholar
  186. 186.
    Miyashita T, Matsui J, Ohtsuka Y et al. Expression of extended polyglutamine sequentially activates initiator and effector caspases. Biochem Biophys Res Commun 1999; 257:724–730.PubMedCrossRefGoogle Scholar
  187. 187.
    Wang GH, Mitsui K, Kotliarova S et al. Caspase activation during apoptotic cell death induced by expanded polyglutamine in N2a cells. Neuroreport 1999; 10:2435–2438.PubMedCrossRefGoogle Scholar
  188. 188.
    Moulder KL, Onodera 0, Burke JR et al. Generation of neuronal intranuclear inclusions by polyglutamine-GFP: Analysis of inclusion clearance and toxicity as a function of polyglutamine length. J Neurosci 1999; 19:705–715.PubMedGoogle Scholar
  189. 189.
    Kouroku Y, Fujita E, Urase K et al. Caspases that are activated during generation of nuclear polyglutamine aggregates are necessary for DNA fragmentation but not sufficient for cell death. J Neurosci Res 2000; 62:547–556.PubMedCrossRefGoogle Scholar
  190. 190.
    Sanchez I, Xu CJ, Juo P et al. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 1999; 22:623–633.PubMedCrossRefGoogle Scholar
  191. 191.
    Li SH, Lam S, Cheng AL et al. Intranuclear huntingtin increases the expression of caspase1 and induces apoptosis. Hum Mol Genet 2000; 9:2859–2867.PubMedCrossRefGoogle Scholar
  192. 192.
    Yasuda S, Inoue K, Hirabayashi M et al. Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodies. Genes Cells 1999; 4:743–756.PubMedCrossRefGoogle Scholar
  193. 193.
    Liu YF. Expression of polyglutamine-expanded huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. J Biol Chem 1998; 273:28873–28877.PubMedCrossRefGoogle Scholar
  194. 194.
    Yoshizawa T, Yamagishi Y, Koseki N et al. Cell cycle arrest enhances the in vitro cellular toxicity of the truncated MachadoJoseph disease gene product with an expanded polyglutamine stretch. Hum Mol Genet 2000; 9:69-78.PubMedCrossRefGoogle Scholar
  195. 195.
    Rich T, Assier E, Skepper J et al. Disassembly of nuclear inclusions in the dividing cell—A novel insight into neurodegeneration. Hum Mol Genet 1999; 8:2451-2459.PubMedCrossRefGoogle Scholar
  196. 196.
    Cancel G, Gourfinkel-An I, Stevanin G et al. Somatic mosaicism of the CAG repeat expansion in spinocerebellar ataxia type 3/Machado-Joseph disease. Human Mutation 1998; 11:23-27.PubMedCrossRefGoogle Scholar
  197. 197.
    Matsuura T, Sasaki H, Yabe I et al. Mosaicism of unstable CAG repeats in the brain of spinocerebellar ataxia type 2. J Neurol 1999; 246:835-839.PubMedCrossRefGoogle Scholar
  198. 198.
    Fernandez-Funez P, de Gouyon B et al. Identification of genes that modify ataxin-l-induced neurodegeneration. Nature 2000; 408:101-106.PubMedCrossRefGoogle Scholar
  199. 199.
    World Federation of Neurology Research Group on Huntington’s Chorea. International Huntington Association and the World Federation of Neurology Research Group on Huntington’s Chorea. Guidelines for the molecular genetics predictive test in Huntington’s disease. J Med Genet 1994; 31:555-559.CrossRefGoogle Scholar
  200. 200.
    Schols L, Szymanski S, Peters S et al. Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet 2000; 107:132-137.PubMedCrossRefGoogle Scholar
  201. 201.
    Restituito S, Thompson RM, Eliet J et al. The polyglutamine expansion in spinocerebellar ataxia type 6 causes a beta subunitspecific enhanced activation of P/Q-type calcium channels in Xenopus oocytes. J Neurosci 2000; 20:6394-6403.PubMedGoogle Scholar
  202. 202.
    Matsuyama Z, Wakamori M, Mori Y et al. Direct alteration of the P/Q-type Ca2+ channel property by polyglutamine expansion in spinocerebellar ataxia 6. J Neurosci 1999;19:RC14.PubMedGoogle Scholar
  203. 203.
    Stevanin G, Durr A, Brice A. Spinocerebellar ataxia 7 (chapter 23). In: Klockgether T, ed. Handbook of ataxia disorders. NY: Marcel Dekker, 2001: 463-486.Google Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Giovanni Stevanin
    • 1
    • 2
  • Alexandra Dürr
    • 1
    • 2
    • 3
  • Alexis Brice
    • 1
    • 2
    • 3
  1. 1.INSERM U289Groupe Hospitalier Pitié SalpêtriéreParisFrance
  2. 2.Institut Fédératif di Recherche des NeurosciencesGroupe Hospitalier Pitié SalpêtriéreParisFrance
  3. 3.Département de Génétique, Cytogénétique et EmbryologieGroupe Hospitalier Pitié SalpêtriéreParisFrance

Personalised recommendations