The Cerebellum

, 4:62 | Cite as

The pathogenesis of spinocerebellar ataxia

  • Arnulf H. KoeppenEmail author
Scientific Papers


Six forms of spinocerebellar ataxia (SCA) are caused by pathological cytosine-adenine-guanine (CAG) trinucleotide repeat expansions in the coding region of the mutated genes. The translated proteins contain abnormally long polyglutamine stretches, and SCA-1, SCA-2, SCA-3/Machado-Joseph disease (MJD), SCA-6, SCA-7, and SCA-17 are “polyglutamine diseases”. Despite their clinical and genetic heterogeneity, the ataxia-causing lesions in the brain invariably affect the “cerebellar module” that is defined as a reciprocal circuitry between the cerebellar cortex, the dentate nuclei, and the inferior olivary nuclei. While the neurons of the basis pontis do not properly belong to this module, pontine atrophy is an important additional lesion in SCA-1, SCA-2, and SCA-7. The descriptive term olivopontocerebellar atrophy (OPCA) applies to these forms whereas SCA-6 is the prototype of “pure” cerebellar cortical or cerebello-olivary atrophy. Purkinje cells have an elaborate dendritic tree, and atrophy of these most remarkable cells has captured the attention of many morphologists. Almost invariably, the loss of Purkinje cells entails retrograde neuronal degeneration in the inferior olivary nuclei. However, SCA-6 is an exception, and many olivary neurons survive. Similarly, stellate, basket, and granule cells do not undergo commensurate retrograde atrophy when Purkinje cells disappear. The dentate nucleus displays “grumose” degeneration in SCA-3/MJD while the cerebellar cortex and the inferior olivary nuclei remain largely unaffected. The role of polyglutamine-containing intranuclear and cytoplasmic inclusion bodies in SCA remains unknown but protein aggregation may be the common step in the pathogenesis of these otherwise rather heterogeneous disorders.

Key words

Atrophy cerebellum inferior olivary nucleus pons pathology spinocerebellar ataxia trinucleotide repeat 


  1. 1.
    Holmes SE, O’Hearn EE, McInnis MG, et al. Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2RB is associated with SCA12. Nat Genet. 1999;23:391–2.PubMedCrossRefGoogle Scholar
  2. 2.
    Matsuura T, Yamagata T, Burgess DL, et al. Large expansion of the ATTCT pentanucleotide repeat in the spinocerebellar ataxia type 10. Nat Genet. 2000;26:191–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Chen D-H, Brkanac Z, Verlinde LMJ, et al. Missense mutations in the regulatory domain of PKCγ: A new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet. 2003;72:839–49.PubMedCrossRefGoogle Scholar
  4. 4.
    Menzel P. Beitrag zur Kenntnis der hereditären Ataxie und Kleinhirnrindenatrophie. Arch Psychiat Nervenkrankh. 1891;22:160–90.CrossRefGoogle Scholar
  5. 5.
    Greenfield JG. The spino-cerebellar degenerations. Oxford: Blackwell Sci Publ; 1954.Google Scholar
  6. 6.
    Mizusawa H, Clark HB, Koeppen AH. Spinocerebellar ataxias. In: Dickson D, editor. Neurodegeneration. The molecular pathology of dementia and movement disorders. Basel: ISN Neuropath Press; 2003. pp 242–56.Google Scholar
  7. 7.
    Ramón-y-Cajal S. Histology of the nervous system of man and vertebrates, vol 1 (trans. from the French by Swanson N, Swanson LW). Oxford: Oxford University Press; 1995. p 758.Google Scholar
  8. 8.
    Ishizawa KI, Lin W-L, Tiseo P, Honer WG, Davies P, Dickson DW. A qualitative and quantitative study of grumose degeneration in progressive supranuclear palsy. J Neuropathol Exp Neurol. 2000;59:513–24.PubMedGoogle Scholar
  9. 9.
    Trottier L, Lutz H, Stevanin G, Imbert G, et a.l Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature. 1995;378:403–6.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    Koeppen AH. The Purkinje cell and its afferents in human hereditary ataxia. J Neuropathol Exp Neurol. 1991;50:505–14.PubMedGoogle Scholar
  12. 12.
    Voogd J, Glickstein M. The anatomy of the cerebellum. Trends Neurosci. 1998;21:370–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Geurtz FJ, De Schutter E, Dieudonné S. Unravelling the cerebellar cortex: cytology and cellular physiology of large-sized interneurons in the granular layer. Cerebellum. 2003;2:290–99.CrossRefGoogle Scholar
  14. 14.
    Holmes G, Stewart TG. On the connection of the inferior olives with the cerebellum in man. Brain. 1908;31:125–37.CrossRefGoogle Scholar
  15. 15.
    Strata P, Rossi F. Plasticity of the olivocerebellar pathway. Trends Neurosci. 1998;21:407–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Oscarsson O. Functional organization of olivary projection to the cerebellar anterior lobe. In: Courville J, de Montigny C, Lamarre Y, editors. The inferior olivary nucleus: Anatomy and physiology. New York: Raven Press; 1980. pp 279–89.Google Scholar
  17. 17.
    Yamashita I, Sasaki H, Yabe I, Fukuzawa T, Nogoshi S, Komeichi K, et al. A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter. Ann Neurol. 2000;48:156–63.PubMedCrossRefGoogle Scholar
  18. 18.
    Brkanac Z, Bylenok L, Fernandez M, Matsushita M, Lipe H, Wolff J, et al. A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter. Arch Neurol. 2002;59:1291–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Abeliovich A, Paylor R, Chen C, Kim JJ, Wehner JM, Tonegawa S. PKCγ mutant mice exhibit mild deficits in spatial and contextual learning. Cell. 1993;75:1263–71.PubMedCrossRefGoogle Scholar
  20. 20.
    Kano M, Hashimoto K, Chen C, Abeliovich A, Aiba A, Kurihara H, et al. Impaired synapse elimination during cerebellar development in PKCγ mutant mice. Cell. 1995;83:1223–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen C, Kano M, Abeliovich A, Chen L, Bao S, Kim JJ, et a.l. Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKCγ mutant mice. Cell. 1995;83:1233–42.PubMedCrossRefGoogle Scholar
  22. 22.
    Baird DH, Hatten ME, Mason CA. Cerebellar target neurons provide a stop signal for afferent neurite extension in vitro. J Neurosci. 1992;12:619–34.PubMedGoogle Scholar
  23. 23.
    Zhang Q, Mason CA. Developmental regulation of mossy fiber afferent interactions with target granule cells. Develop Biol. 1998;195:75–87.PubMedCrossRefGoogle Scholar
  24. 24.
    Rabacchi SA, Solowska JM, Kruk B, Luo Y, Raper JA, et a.l. Collapsin-1/semaphorin-III/D is regulated developmentally in Purkinje cells and collapses pontocerebellar mossy fiber neuronal growth cones. J Neurosci. 1999;19:4437–48.PubMedGoogle Scholar
  25. 25.
    Solowska JM, Mazurek A, Weinberger L, Bair DH. Pontocerebellar axon guidance: Neuropilin-1and semaphorin 3A-sensitivity gradients across basilar pontine nuclei and semaphorin 3A variation across cerebellum. Mol Cell Neurosci. 2002;21:266–84.PubMedCrossRefGoogle Scholar
  26. 26.
    Mason CA, Gregory E. Postnatal maturation of cerebellar mossy and climbing fibers: Transient expression of dual features on single axons. J Neurosci. 1984;4:1715–35.PubMedGoogle Scholar
  27. 27.
    Lapresle J, Ben Hamida M. The dentato-olivary pathway. Arch Neurol. 1970;22:135–43.PubMedGoogle Scholar
  28. 28.
    Hanihara T, Amano N, Takahashi T, Itoh Y, Yagashita S. Hypertrophy of the inferior olivary nucleus in patients with progressive supranuclear palsy. Eur Neurol. 1998;39:97–102.PubMedCrossRefGoogle Scholar
  29. 29.
    Robitaille Y, Lopes-Cendes I, Becher M, Rouleau G, Clark AW. The neuropathology of CAG repeat diseases: Review and update of genetic and molecular features. Brain Pathol. 1997;7:901–26.PubMedCrossRefGoogle Scholar
  30. 30.
    Koeppen AH, Barron KD, Dentinger MP. Olivary hypertrophy in man. In: Courville J, DeMontigny C, Lamarre Y, editors. The inferior olivary nucleus: Anatomy and physiology. New York: Raven Press; 1980. pp 309–14.Google Scholar
  31. 31.
    Koeppen AH, Dickson AC, Lamarche JB, Robitaille Y. Synapses in the hereditary ataxias. J Neuropathol Exp Neurol. 1999;58:748–64.PubMedGoogle Scholar
  32. 32.
    Ishikawa K, Owada K, Ishida K, Fujigasaki H, Shun Li M, et al. Cytoplasmic and nuclear polyglutamine aggregates in SCA6 Purkinje cells. Neurology. 2001;56:1753–6.PubMedGoogle Scholar
  33. 33.
    Huynh DP, Del Bigio MR, Ho DH, Pulst S-M. Expression of ataxin-2 in brains of normal individuals and patients with Alzheimer’s disease and spinocerebellar ataxia 2. Ann Neurol. 1999;45:232–41.PubMedCrossRefGoogle Scholar
  34. 34.
    Koyano S, Uchihara T, Fujigasaki H, Nakamura A, Yagashita S, Iwabuchi K. Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study. Neurosci Lett. 1999;273:117–20.PubMedCrossRefGoogle Scholar
  35. 35.
    Pang JT, Giunti P, Chamberlain S, An SF, Vitaliani R, Scaravilli T, et al. Neuronal intranuclear inclusions in SCA2: A genetic, morphological and immunohistochemical study of two cases. Brain. 2002;125:656–63.PubMedCrossRefGoogle Scholar
  36. 36.
    Holmberg M, Duyckerts C, Dürr 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;7:913–18.PubMedCrossRefGoogle Scholar
  37. 37.
    Okazawa H. Polyglutamine diseases: a transcription disorder? Cell Mol Life Sci. 2003;60:1247–39.CrossRefGoogle Scholar
  38. 38.
    Kimura Y, Kakizuka A. Polyglutamine diseases and molecular chaperones. IUBMB Life. 2003;55:337–45.PubMedCrossRefGoogle Scholar
  39. 39.
    Michalek A, Van Broeckhoven C. Pathogenesis of polyglutamine disorders: Aggregation revisited. Hum Mol Genet. 2003;12:R173–86.CrossRefGoogle Scholar
  40. 40.
    Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB. Ataxin-1 nuclear localization and aggregation: Role in polyglutamine-induced disease in SCA-1 transgenic mice. Cell. 1998;95:41–53.PubMedCrossRefGoogle Scholar
  41. 41.
    Evert BO, Wüllner U, Klockgether T. Cell death in polyglutamine diseases. Cell Tissue Res. 2000;301:189–204.PubMedCrossRefGoogle Scholar
  42. 42.
    Lipinski MM, Yuan J. Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharmacol. 2004;4:85–90.PubMedCrossRefGoogle Scholar
  43. 43.
    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.PubMedCrossRefGoogle Scholar
  44. 44.
    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.PubMedCrossRefGoogle Scholar
  45. 45.
    Schwaller B, Meyer M, Schiffmann S. ‘New’ functions for ‘old’ proteins: the role of calcium-binding proteins calbindin D-28k, calretinin and parvalbumin, in cerebellar physiology. Studies with knockout mice. Cerebellum. 2002;1:241–58.PubMedCrossRefGoogle Scholar

Copyright information

© Taylor & Francis Group Ltd 2005

Authors and Affiliations

  1. 1.Neurology ServiceVA Medical CenterAlbany
  2. 2.Pathology ServiceVA Medical CenterAlbany
  3. 3.Albany Medical CollegeAlbanyUSA

Personalised recommendations