Skip to main content
SpringerLink
Log in

DRPLA: Recent Advances in Research Using Transgenic Mouse Models

  • Protocol
  • First Online:
Trinucleotide Repeat Protocols

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1010))

Abstract

Dentatorubral-pallidoluysian atrophy (DRPLA) is one form of trinucleotide repeat disease, which has a high prevalence rate in the Japanese population. Our group established DRPLA transgenic mice harboring a single copy of a full-length human mutant DRPLA gene with 76 CAG repeats (Q76 mice). Q76 mice showed no obvious neurological phenotype but showed somatic and intergenerational instabilities of CAG repeats which closely resembled those in human DRPLA. During the breeding of Q76 mice, we serendipitously generated an additional strain with 129 repeats by “en masse” expansion of CAG repeats (Q129 mice). These two substrains are ideal models for the investigation of CAG-repeat-dependent pathogenesis of DRPLA, because they have the same genetic background except for the length of CAG repeats. Q129 mice showed a marked neurological phenotype and massive neuronal intranuclear accumulation (NIA) of mutant proteins, but showed no obvious neuronal loss. Through detailed investigations of these two substrains, we believe that “neuronal dysfunction without neuronal loss” is the key concept in the pathogenesis of DRPLA.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

References

  1. Smith JK (1975) Dentatorubropallidoluysian atrophy, in Handbook of clinical neurology. North-Holland, Amsterdam, The Netherlands, pp 519–534

    Google Scholar 

  2. Smith JK, Gonda VE et al (1958) Unusual form of cerebellar ataxia; combined dentato-rubral and pallido-Luysian degeneration. Neurology 8:205–209

    Article  PubMed  CAS  Google Scholar 

  3. Naito H, Izawa K et al (1972) Two families of progressive myoclonus epilepsy with Mendelian dominant heredity. Seishin Shinkeigaku Zasshi 74:871–897

    PubMed  CAS  Google Scholar 

  4. Koide R, Ikeuchi T et al (1994) Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet 6:9–13

    Article  PubMed  CAS  Google Scholar 

  5. Nagafuchi S, Yanagisawa H et al (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 6:14–18

    Article  PubMed  CAS  Google Scholar 

  6. La Spada AR, Wilson EM et al (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79

    Article  PubMed  Google Scholar 

  7. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983

    Google Scholar 

  8. Orr HT, Chung MY et al (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 4:221–226

    Article  PubMed  CAS  Google Scholar 

  9. Imbert G, Saudou F et al (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 14:285–291

    Article  PubMed  CAS  Google Scholar 

  10. Pulst SM, Nechiporuk A et al (1996) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14:269–276

    Article  PubMed  CAS  Google Scholar 

  11. Sanpei K, Takano H et al (1996) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet 14:277–284

    Article  PubMed  CAS  Google Scholar 

  12. Kawaguchi Y, Okamoto T et al (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228

    Article  PubMed  CAS  Google Scholar 

  13. Zhuchenko O, Bailey J et al (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet 15:62–69

    Article  PubMed  CAS  Google Scholar 

  14. Lindblad K, Savontaus ML et al (1996) An expanded CAG repeat sequence in spinocerebellar ataxia type 7. Genome Res 6:965–971

    Article  PubMed  CAS  Google Scholar 

  15. David G, Abbas N et al (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet 17:65–70

    Article  PubMed  CAS  Google Scholar 

  16. Koide R, Kobayashi S et al (1999) A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease? Hum Mol Genet 8:2047–2053

    Article  PubMed  CAS  Google Scholar 

  17. Nakamura K, Jeong SY et al (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet 10:1441–1448

    Article  PubMed  CAS  Google Scholar 

  18. Komure O, Sano A et al (1995) DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation. Neurology 45:143–149

    Article  PubMed  CAS  Google Scholar 

  19. David G, Durr A et al (1998) Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). Hum Mol Genet 7:165–170

    Article  PubMed  CAS  Google Scholar 

  20. Ikeuchi T, Koide R et al (1995) Dentatorubral-pallidoluysian atrophy: clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat. Ann Neurol 37:769–775

    Article  PubMed  CAS  Google Scholar 

  21. Gouw LG, Castaneda MA et al (1998) Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission. Hum Mol Genet 7:525–532

    Article  PubMed  CAS  Google Scholar 

  22. Davies SW, Turmaine M et al (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548

    Article  PubMed  CAS  Google Scholar 

  23. DiFiglia M, Sapp E et al (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993

    Article  PubMed  CAS  Google Scholar 

  24. Skinner PJ, Koshy BT et al (1997) Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389:971–974

    Article  PubMed  CAS  Google Scholar 

  25. Paulson HL, Perez MK et al (1997) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19:333–344

    Article  PubMed  CAS  Google Scholar 

  26. Holmberg M, Duyckaerts C et al (1998) Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions. Hum Mol Genet 7:913–918

    Article  PubMed  CAS  Google Scholar 

  27. Hayashi Y, Kakita A et al (1998) Hereditary dentatorubral-pallidoluysian atrophy: detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain. Acta Neuropathol 96:547–552

    Article  PubMed  CAS  Google Scholar 

  28. Igarashi S, Koide R et al (1998) Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet 18:111–117

    Article  PubMed  CAS  Google Scholar 

  29. Ross CA (1997) Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron 19:1147–1150

    Article  PubMed  CAS  Google Scholar 

  30. Schilling G, Wood JD et al (1999) Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA. Neuron 24:275–286

    Article  PubMed  CAS  Google Scholar 

  31. Sisodia SS (1998) Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial? Cell 95:1–4

    Article  PubMed  CAS  Google Scholar 

  32. Saudou F, Finkbeiner S et al (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66

    Article  PubMed  CAS  Google Scholar 

  33. Yamada M, Wood JD et al (2001) Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral-pallidoluysian atrophy. Ann Neurol 49:14–23

    Article  PubMed  CAS  Google Scholar 

  34. Yamada M, Tsuji S et al (2000) Pathology of CAG repeat diseases. Neuropathology 20:319–325

    Article  PubMed  CAS  Google Scholar 

  35. Yamada M, Hayashi S et al (2001) Involvement of the cerebral cortex and autonomic ganglia in Machado-Joseph disease. Acta Neuropathol 101:140–144

    PubMed  CAS  Google Scholar 

  36. Sato T, Oyake M et al (1999) Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients. Hum Mol Genet 8:99–106

    Article  PubMed  CAS  Google Scholar 

  37. Sato T, Miura M et al (2009) Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice. Hum Mol Genet 18:723–736

    Article  PubMed  CAS  Google Scholar 

  38. Tanaka F, Sobue G et al (1996) Differential pattern in tissue-specific somatic mosaicism of expanded CAG trinucleotide repeats in dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and X-linked recessive spinal and bulbar muscular atrophy. J Neurol Sci 135:43–50

    Article  PubMed  CAS  Google Scholar 

  39. Takano H, Onodera O et al (1996) Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: cellular population-dependent dynamics of mitotic instability. Am J Hum Genet 58:1212–1222

    PubMed  CAS  Google Scholar 

  40. Sakai K, Yamada M et al (2006) Neuronal atrophy and synaptic alteration in a mouse model of dentatorubral-pallidoluysian atrophy. Brain 129:2353–2362

    Article  PubMed  Google Scholar 

  41. Shimohata T, Nakajima T et al (2000) Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet 26:29–36

    Article  PubMed  CAS  Google Scholar 

  42. Nucifora FC Jr, Sasaki M et al (2001) Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291:2423–2428

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Kazushi Suzuki & Shoji Tsuji

  2. Brain Research Institute, Niigata University, Chuo-ku, Japan

    Toshiya Sato

  3. Department of Clinical Research, Saigata National Hospital, National Hospital Organization, Joetsu City, Niigata, Japan

    Mitsunori Yamada

  4. Brain Research Institute, Niigata University, Chuo-ku, Niigata, Japan

    Hitoshi Takahashi

Authors
  1. Kazushi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiya Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mitsunori Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hitoshi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shoji Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Life Sciences Division, Lawrence Berkeley National Laboratory, Cyclotron Road, MS-977 1, Berkeley, 94720, California, USA

    Yoshinori Kohwi

  2. Life Sciences Division, Lawrence Berkeley National Laboratory, Cyclotron Road, MS-83 1, Berkeley, 94720, California, USA

    Cynthia T. McMurray

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer New York

About this protocol

Cite this protocol

Suzuki, K., Sato, T., Yamada, M., Takahashi, H., Tsuji, S. (2013). DRPLA: Recent Advances in Research Using Transgenic Mouse Models. In: Kohwi, Y., McMurray, C. (eds) Trinucleotide Repeat Protocols. Methods in Molecular Biology, vol 1010. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-411-1_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-411-1_18

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-410-4

  • Online ISBN: 978-1-62703-411-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation