Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine

Nature Medicine volume 8, pages 143–149 (2002)Cite this article

An Erratum to this article was published on 01 March 2002

Abstract

An expanded polyglutamine domain in huntingtin underlies the pathogenic events in Huntington disease (HD), characterized by chorea, dementia and severe weight loss, culminating in death. Transglutaminase (TGase) may be critical in the pathogenesis, via cross-linking huntingtin. Administration of the TGase competitive inhibitor, cystamine, to transgenic mice expressing exon 1 of huntingtin containing an expanded polyglutamine repeat, altered the course of their HD-like disease. Cystamine given intraperitoneally entered brain where it inhibited TGase activity. When treatment began after the appearance of abnormal movements, cystamine extended survival, reduced associated tremor and abnormal movements and ameliorated weight loss. Treatment did not influence the appearance or frequency of neuronal nuclear inclusions. Unexpectedly, cystamine treatment increased transcription of one of the two genes shown to be neuroprotective for polyglutamine toxicity in Drosophila, dnaj (also known as HDJ1 and Hsp40 in humans and mice, respectively). Inhibition of TGase provides a new treatment strategy for HD and other polyglutamine diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Partial prevention of movement disorder in R6/2 mice treated with cystamine.
Figure 2: Intranuclear inclusions in HD transgenic mice with and without cystamine treatment.
Figure 3: Cluster analysis of brain gene transcripts increased following cystamine treatment of R6/2 mice.

Similar content being viewed by others

References

  1. Green, H. Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism. Cell 74, 955–956 (1993).

    Article  CAS  Google Scholar 

  2. Lorand, L. Neurodegenerative diseases and transglutaminase. Proc. Natl. Acad. Sci. USA 93, 14310–1433 (1996).

    Article  CAS  Google Scholar 

  3. Lorand, L. DRPLA aggregation and transglutaminase, revisited. Nature Genet. 20, 231–233 (1998).

    Article  CAS  Google Scholar 

  4. Perutz, M.F. Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends Biochem. Sci. 24, 58–63 (1999).

    Article  CAS  Google Scholar 

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

  6. Kahlem, P., Green, H. & Djian, P. Transglutaminase action imitates Huntington's Disease: Selective polymerization of huntingtin containing expanded polyglutamine. Mol. Cell 1, 595–601 (1998).

    Article  CAS  Google Scholar 

  7. Karpuj, M.V. et al. Transglutaminase aggregates huntingtin into non-amyloidogenic polymers and its enzymatic activity is increased in Huntington's disease brain nuclei. Proc. Natl. Acad. Sci. USA 96, 7388–7393 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Lorand, L. Neurodegenerative diseases and transglutaminase. Proc. Natl. Acad. Sci. USA 93, 14310–14313 (1997).

    Article  Google Scholar 

  10. Lesort, M., Chun. W., Johnson, G.V. & Ferrante, R.J. Tissue transglutaminase is increased in Huntington's disease brain. J. Neurochem. 73, 2018–2027 (1999).

    CAS  PubMed  Google Scholar 

  11. Folk, J.E. Transglutaminases. Ann. Rev. Biochem. 49, 517–531 (1980).

    Article  CAS  Google Scholar 

  12. Lorand, L. & Conrad S. Transglutaminases. Mol. Cell. Biochem. 58, 25–26 (1984).

    Google Scholar 

  13. Lorand, L. et al. Specificity of guinea pig liver transglutaminase for amine substrates. Biochemistry 18, 1756–1765 (1979).

    Article  CAS  Google Scholar 

  14. Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 (1996).

    Article  CAS  Google Scholar 

  15. Ona, V. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263–267 (1999).

    Article  CAS  Google Scholar 

  16. Davies, S.W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Becher, M.W. et al. Intranuclear neuronal inclusions in Huntington's disease and DRPLA: Correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol. Disease 4, 387–397 (1998).

    Article  CAS  Google Scholar 

  19. Huang, C.C. et al. Amyloid formation by mutant hutingtin: threshold, progressivity, and recruitment of polyglutamine proteins. Somatic Cell Mol. Genet. 24, 217–233 (1998).

    Article  CAS  Google Scholar 

  20. Zainelli, G., Ross, C.A., Troncoso, J.C. & Muma, N.A. Transglutaminase catalyzed cross-links in intranuclear inclusions. Soc. Neurosci. Absracts 26, 1297 (2000).

  21. Ordway J.M. et al. Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype. Cell 91, 753–763 (1997).

    Article  CAS  Google Scholar 

  22. Saudou, P., Finkbeiner, S., Devys, D. & Greenberg, M. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).

    Article  CAS  Google Scholar 

  23. Yamamoto, A. Lucas, J.J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57–66 (2000).

    Article  CAS  Google Scholar 

  24. Orr, H. & Zoghbi, H. Reversing neurodegeneration: a promise unfolds. Cell 101, 1–4, 2000.

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

    Article  CAS  Google Scholar 

  26. Folk, J.E. & Cole, P.W. Transglutaminase: mechanistic features of the active site as determined by kinetic and inhibitor studies. Biochim. Biophys. Acta. 122, 244–264 (1966).

    Article  CAS  Google Scholar 

  27. Curtis, C.G. & Lorand, L. Fibrin-stabilizing factor (factor XIII). Methods Enzymol. 45, 177–191 (1976).

    Article  CAS  Google Scholar 

  28. Cooper, A.J. et al. Polyglutamine domains are substrates of tissue translutaminase: does transglutaminase play a role in expanded CAG/poly Q neurodegenerative diseases? J. Neurochem. 69, 431–434 (1997).

    Article  CAS  Google Scholar 

  29. Bates,G., Mangiarini, L. & Davies, S. Transgenic mice in the study of polyglutamine disease. Brain Pathol. 8, 699–714 (1998).

    Article  Google Scholar 

  30. Sathasivam, K. et al. Formation of polyglutamine inclusions in non-CNS tissue. Hum. Mol. Genet. 8, 813–822 (1999).

    Article  CAS  Google Scholar 

  31. Yu, S.P., Yeh, C., Strasser, U., Tian, M. & Choi, D.W. NMDA receptor–mediated K+ efflux and neuronal apoptosis. Science 284, 336–339 (1999).

    Article  CAS  Google Scholar 

  32. Isupov, M.N. et al. Substrate binding is required for assembly of the active conformation of the catalytic site in Ntn amidotransferases: evidence from the 1.8 A crystal structure of the glutaminase domain of glucosamine 6-phosphate synthase. Structure 4, 801–810 (1996).

    Article  CAS  Google Scholar 

  33. Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nature Med. 4, 713–717 (1998).

    Article  CAS  Google Scholar 

  34. Newcomb, R., Sun, X., Taylor, L., Curthoys, N. & Giffard, R.G. Increased production of extracellular glutamate by the mitochondrial glutaminase following neuronal death, J. Biol. Chem. 272, 11276–82 (1997).

    Article  CAS  Google Scholar 

  35. Luthi-Carter, R. et al. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum. Mol. Genet. 9, 1259–1271 (2000).

    Article  CAS  Google Scholar 

  36. Voehringer, D. et al. Gene microarray identification of redox and mitochondrial elements that control resistance or sensitivity to apoptosis. Proc. Natl Acad Sci USA 97, 2680–2685 (2000).

    Article  CAS  Google Scholar 

  37. Kazemi Esfarjani, P., Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837–1840 (2000).

    Article  CAS  Google Scholar 

  38. Scheufler, C. et al. Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 101, 199–210 (2000).

    Article  CAS  Google Scholar 

  39. Kobayashi, Y. et al. Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J. Biol. Chem. 275, 8772–8778 (2000).

    Article  CAS  Google Scholar 

  40. Cummings, C.J. et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature Genet. 19, 148–154 (1998).

    Article  CAS  Google Scholar 

  41. Chabas, D. et al. The influence of the pro-inflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001).

    Article  CAS  Google Scholar 

  42. Ferrante, R.J. et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J. Neurosci. 20, 4389–4397 (2000).

    Article  CAS  Google Scholar 

  43. Chen, M. et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Med. 6, 797–801 (2000).

    Article  CAS  Google Scholar 

  44. Clarke, G. et al. A one-hit model of cell death in inherited neuronal degenerations. Nature 406, 195–199 (2000).

    Article  CAS  Google Scholar 

  45. Jeitner, T.M. et al. N-(γ-L-glutamyl)-l-lysine is increased in cerebrospinal fluid of patients with Huntington's disease. J. Neurochem. 79, 1109–1112 (2001).

    Article  CAS  Google Scholar 

  46. Springer, J.E., Azbill, R.D. & Knapp, P.E. Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nature Med. 5, 943–946 (1999).

    Article  CAS  Google Scholar 

  47. Rittling, S.R. & Feng, F. Detection of mouse osteopontin by western blotting. Biochem. Biophys Res Commun 250, 287–292 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J.A. Kotzuk for technical expertise. This work was supported by the Hereditary Disease Foundation (to M.B. and L.S.) and the NIH (Javits Grant to L.S., R0118235).

Author information

Authors and Affiliations

  1. Department of Neurological Sciences, Stanford University, Stanford, California, USA

    Marcela V. Karpuj, Dorothee Chabas, Sawsan Youssef, Rosetta Pedotti, Dennis Mitchell & Lawrence Steinman

  2. Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA

    Mark W. Becher

  3. Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington, Kentucky, USA

    Joe E. Springer

Authors
  1. Marcela V. Karpuj
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark W. Becher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joe E. Springer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dorothee Chabas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sawsan Youssef
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rosetta Pedotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dennis Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lawrence Steinman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lawrence Steinman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Karpuj, M., Becher, M., Springer, J. et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat Med 8, 143–149 (2002). https://doi.org/10.1038/nm0202-143

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0202-143

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing