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.

Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1

Nature volume 452, pages 713–718 (2008)Cite this article

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: ATXN1(S776D) but not ATXN1(S776A) interacts with RBM17.
Figure 2: Enhanced interaction of RBM17 and ATXN1 depends on S776 phosphorylation and polyglutamine tract expansion.
Figure 3: RBM17 contributes to polyglutamine-expanded ATXN1 toxicity in the Drosophila eye.
Figure 4: Polyglutamine expansion enhances RBM17 incorporation into the large ATXN1 native protein complexes.
Figure 5: Rbm17 and Cic form two distinct protein complexes that compete with each other.
Figure 6: Loss of wild-type Atxn1 function worsens SCA1 neuropathology in mice.

References

  1. Orr, H. T. & Zoghbi, H. Y. Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30, 575–621 (2007)

    Article  CAS  Google Scholar 

  2. Harjes, P. & Wanker, E. E. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem. Sci. 28, 425–433 (2003)

    Article  CAS  Google Scholar 

  3. Li, S. H. & Li, X. J. Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet. 20, 146–154 (2004)

    Article  Google Scholar 

  4. Matilla, A. et al. Mice lacking ataxin-1 display learning deficits and decreased hippocampal paired-pulse facilitation. J. Neurosci. 18, 5508–5516 (1998)

    Article  CAS  Google Scholar 

  5. Yeh, S. et al. Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proc. Natl Acad. Sci. USA 99, 13498–13503 (2002)

    Article  CAS  ADS  Google Scholar 

  6. Zeitlin, S., Liu, J. P., Chapman, D. L., Papaioannou, V. E. & Efstratiadis, A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nature Genet. 11, 155–163 (1995)

    Article  CAS  Google Scholar 

  7. Kiehl, T. R. et al. Generation and characterization of Sca2 (ataxin-2) knockout mice. Biochem. Biophys. Res. Commun. 339, 17–24 (2006)

    Article  CAS  Google Scholar 

  8. Klement, I. A. et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95, 41–53 (1998)

    Article  CAS  Google Scholar 

  9. Tsuda, H. et al. The AXH domain of ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/senseless proteins. Cell 122, 633–644 (2005)

    Article  CAS  Google Scholar 

  10. Emamian, E. S. et al. Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38, 375–387 (2003)

    Article  CAS  Google Scholar 

  11. McManamny, P. et al. A mouse model of spinal and bulbar muscular atrophy. Hum. Mol. Genet. 11, 2103–2111 (2002)

    Article  CAS  Google Scholar 

  12. Katsuno, M. et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35, 843–854 (2002)

    Article  CAS  Google Scholar 

  13. Chevalier-Larsen, E. S. et al. Castration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy. J. Neurosci. 24, 4778–4786 (2004)

    Article  CAS  Google Scholar 

  14. Sopher, B. L. et al. Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41, 687–699 (2004)

    Article  CAS  Google Scholar 

  15. Graham, R. K. et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125, 1179–1191 (2006)

    Article  CAS  Google Scholar 

  16. Warby, S. C. et al. Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo. Hum. Mol. Genet. 14, 1569–1577 (2005)

    Article  CAS  Google Scholar 

  17. Luo, S., Vacher, C., Davies, J. E. & Rubinsztein, D. C. Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J. Cell Biol. 169, 647–656 (2005)

    Article  CAS  Google Scholar 

  18. Steffan, J. S. et al. SUMO modification of Huntingtin and Huntington’s disease pathology. Science 304, 100–104 (2004)

    Article  CAS  ADS  Google Scholar 

  19. Fernandez-Funez, P. et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106 (2000)

    Article  CAS  ADS  Google Scholar 

  20. Lim, J. et al. A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 125, 801–814 (2006)

    Article  CAS  Google Scholar 

  21. Lein, E. S. et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007)

    Article  CAS  ADS  Google Scholar 

  22. Burright, E. N. et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82, 937–948 (1995)

    Article  CAS  Google Scholar 

  23. Lam, Y. C. et al. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127, 1335–1347 (2006)

    Article  CAS  Google Scholar 

  24. Watase, K. et al. A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34, 905–919 (2002)

    Article  CAS  Google Scholar 

  25. Bowman, A. B. et al. Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nature Genet. 39, 373–379 (2007)

    Article  CAS  Google Scholar 

  26. Serra, H. G. et al. RORα-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell 127, 697–708 (2006)

    Article  CAS  Google Scholar 

  27. Sampath, J. et al. Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells. Am. J. Pathol. 163, 1781–1790 (2003)

    Article  CAS  Google Scholar 

  28. Chaouki, A. S. & Salz, H. K. Drosophila SPF45: A bifunctional protein with roles in both splicing and DNA repair. PLoS Genet 2, e178 (2006)

    Article  Google Scholar 

  29. Lallena, M. J., Chalmers, K. J., Llamazares, S., Lamond, A. I. & Valcarcel, J. Splicing regulation at the second catalytic step by Sex-lethal involves 3′ splice site recognition by SPF45. Cell 109, 285–296 (2002)

    Article  CAS  Google Scholar 

  30. Yue, S., Serra, H. G., Zoghbi, H. Y. & Orr, H. T. The spinocerebellar ataxia type 1 protein, ataxin-1, has RNA-binding activity that is inversely affected by the length of its polyglutamine tract. Hum. Mol. Genet. 10, 25–30 (2001)

    Article  CAS  Google Scholar 

  31. Zuccato, C. et al. Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease. J. Neurosci. 27, 6972–6983 (2007)

    Article  CAS  Google Scholar 

  32. Auerbach, W. et al. The HD mutation causes progressive lethal neurological disease in mice expressing reduced levels of huntingtin. Hum. Mol. Genet. 10, 2515–2523 (2001)

    Article  CAS  Google Scholar 

  33. Van Raamsdonk, J. M. et al. Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease. Hum. Mol. Genet. 14, 1379–1392 (2005)

    Article  CAS  Google Scholar 

  34. Leavitt, B. R. et al. Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo. Am. J. Hum. Genet. 68, 313–324 (2001)

    Article  CAS  Google Scholar 

  35. Cattaneo, E., Zuccato, C. & Tartari, M. Normal huntingtin function: an alternative approach to Huntington’s disease. Nature Rev. Neurosci. 6, 919–930 (2005)

    Article  CAS  Google Scholar 

  36. Thomas, P. S. et al. Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy. Hum. Mol. Genet. 15, 2225–2238 (2006)

    Article  CAS  Google Scholar 

  37. Zuccato, C. et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nature Genet. 35, 76–83 (2003)

    Article  CAS  Google Scholar 

  38. Friedman, M. J. et al. Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration. Nature Neurosci. 10, 1519–1528 (2007)

    Article  CAS  Google Scholar 

  39. Li, A., Piccardo, P., Barmada, S. J., Ghetti, B. & Harris, D. A. Prion protein with an octapeptide insertion has impaired neuroprotective activity in transgenic mice. EMBO J. 26, 2777–2785 (2007)

    Article  CAS  Google Scholar 

  40. Harris, D. A. & True, H. L. New insights into prion structure and toxicity. Neuron 50, 353–357 (2006)

    Article  CAS  Google Scholar 

  41. Shen, J. & Kelleher, R. J. The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl Acad. Sci. USA 104, 403–409 (2007)

    Article  CAS  ADS  Google Scholar 

  42. Van Broeck, B., Van Broeckhoven, C. & Kumar-Singh, S. Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches. Neurodegener. Dis. 4, 349–365 (2007)

    Article  CAS  Google Scholar 

  43. Rual, J. F. et al. Towards a proteome-scale map of the human protein–protein interaction network. Nature 437, 1173–1178 (2005)

    Article  CAS  ADS  Google Scholar 

Download references

Acknowledgements

We are grateful to M. Vidal for the human ORFeome and yeast two-hybrid screening technology; J. Valcárcel and W. Perry for anti-RBM17 antibody; H. Salz for dRBM17 mutant flies; Y. He for generating the RBM17 transgenic flies; H. Bellen and H. Jafar-Nejad, and members of the Zoghbi laboratory, for comments on the manuscript; and V. Brandt for editorial input. This research was supported by the NIH grants (H.Y.Z., H.T.O., M.V.), cores of the BCM-MRDDRC, the Ellison Foundation and the W.M. Keck Foundation awarded to M.V. and D.E.H., and Institute Sponsored Research from the DFCI Strategic Initiative in support of Center for Cancer Systems Biology. H.Y.Z. is an investigator with the Howard Hughes Medical Institute.

Author Contributions J.L. and H.Y.Z. designed the experiments. J.L. performed the majority of the experiments with the exception of the mouse genetic interaction in Fig. 6a, b (J.C.-B. and A.B.B.), and immunoprecipitation assays in Figs 1d and 5a (P.J.-N.). R.R. provided technical assistance performing gel-filtration chromatography. D.E.H. provided the ORFeome library and advice. Data analyses and interpretation were conducted by J.L., H.T.O. and H.Y.Z. J.L. and H.Y.Z. wrote the paper.

Author information

Author notes

  1. Aaron B. Bowman

    Present address: Present address: Department of Neurology, Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37232, USA.,

Authors and Affiliations

  1. Department of Molecular and Human Genetics,,

    Janghoo Lim, Paymaan Jafar-Nejad, Aaron B. Bowman & Huda Y. Zoghbi

  2. Interdepartmental program in Cell and Molecular Biology,,

    Juan Crespo-Barreto & Huda Y. Zoghbi

  3. Departments of Pediatrics and Neuroscience,,

    Huda Y. Zoghbi

  4. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA,

    Ronald Richman & Huda Y. Zoghbi

  5. Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA,

    David E. Hill

  6. Department of Biochemistry, Department of Laboratory Medicine and Pathology, Institute of Human Genetics, Biophysics and Molecular Biology, University of Minnesota, Minneapolis, Minnesota 55455, USA,

    Harry T. Orr

Authors
  1. Janghoo Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juan Crespo-Barreto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paymaan Jafar-Nejad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aaron B. Bowman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ronald Richman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David E. Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Harry T. Orr
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huda Y. Zoghbi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huda Y. Zoghbi.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S16 with Legends. The Supplementary Figures include additional experimental results. (PDF 5021 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lim, J., Crespo-Barreto, J., Jafar-Nejad, P. et al. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452, 713–718 (2008). https://doi.org/10.1038/nature06731

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06731

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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