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RNA toxicity is a component of ataxin-3 degeneration in Drosophila

Nature volume 453, pages 1107–1111 (2008)Cite this article

Abstract

Polyglutamine (polyQ) diseases are a class of dominantly inherited neurodegenerative disorders caused by the expansion of a CAG repeat encoding glutamine within the coding region of the respective genes1. The molecular and cellular pathways underlying polyQ-induced neurodegeneration are the focus of much research, and it is widely considered that toxic activities of the protein, resulting from the abnormally long polyQ tract, cause pathogenesis2,3. Here we provide evidence for a pathogenic role of the CAG repeat RNA in polyQ toxicity using Drosophila. In a Drosophila screen for modifiers of polyQ degeneration induced by the spinocerebellar ataxia type 3 (SCA3) protein ataxin-3, we isolated an upregulation allele of muscleblind (mbl), a gene implicated in the RNA toxicity of CUG expansion diseases4,5,6. Further analysis indicated that there may be a toxic role of the RNA in polyQ-induced degeneration. We tested the role of the RNA by altering the CAG repeat sequence to an interrupted CAACAG repeat within the polyQ-encoding region; this dramatically mitigated toxicity. In addition, expression of an untranslated CAG repeat of pathogenic length conferred neuronal degeneration. These studies reveal a role for the RNA in polyQ toxicity, highlighting common components in RNA-based and polyQ-protein-based trinucleotide repeat expansion diseases.

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Figure 1: Upregulation of mbl enhances ataxin-3 toxicity.
Figure 2: Interruptions of the CAG repeat mitigate SCA3 protein pathogenesis.
Figure 3: Untranslated CAG repeats induce progressive neural dysfunction.

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References

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

    Article  CAS  Google Scholar 

  2. Gatchel, J. R. & Zoghbi, H. Y. Diseases of unstable repeat expansion: mechanisms and common principles. Nature Rev. Genet. 6, 743–755 (2005)

    Article  CAS  Google Scholar 

  3. Ross, C. A. & Poirier, M. A. What is the role of protein aggregation in neurodegeneration? Nature Rev. Mol. Cell Biol. 6, 891–898 (2005)

    Article  CAS  Google Scholar 

  4. Jiang, H., Mankodi, A., Swanson, M. S., Moxley, R. T. & Thornton, C. A. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum. Mol. Genet. 13, 3079–3088 (2004)

    Article  CAS  Google Scholar 

  5. Mankodi, A. et al. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum. Mol. Genet. 10, 2165–2170 (2001)

    Article  CAS  Google Scholar 

  6. Miller, J. W. et al. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 19, 4439–4448 (2000)

    Article  CAS  Google Scholar 

  7. Warrick, J. M. et al. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93, 939–949 (1998)

    Article  CAS  Google Scholar 

  8. Begemann, G. et al. muscleblind, a gene required for photoreceptor differentiation in Drosophila, encodes novel nuclear Cys3His-type zinc-finger-containing proteins. Development 124, 4321–4331 (1997)

    CAS  PubMed  Google Scholar 

  9. Artero, R. et al. The muscleblind gene participates in the organization of Z-bands and epidermal attachments of Drosophila muscles and is regulated by Dmef2. Dev. Biol. 195, 131–143 (1998)

    Article  CAS  Google Scholar 

  10. Kanadia, R. N. et al. Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc. Natl Acad. Sci. USA 103, 11748–11753 (2006)

    Article  ADS  CAS  Google Scholar 

  11. Kino, Y. et al. Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats. Hum. Mol. Genet. 13, 495–507 (2004)

    Article  CAS  Google Scholar 

  12. Ho, T. H. et al. Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy. J. Cell Sci. 118, 2923–2933 (2005)

    Article  CAS  Google Scholar 

  13. Ranum, L. P. & Cooper, T. A. RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29, 259–277 (2006)

    Article  CAS  Google Scholar 

  14. Wheeler, T. M. & Thornton, C. A. Myotonic dystrophy: RNA-mediated muscle disease. Curr. Opin. Neurol. 20, 572–576 (2007)

    Article  CAS  Google Scholar 

  15. Philips, A. V., Timchenko, L. T. & Cooper, T. A. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737–741 (1998)

    Article  ADS  CAS  Google Scholar 

  16. McLeod, C. J., O’Keefe, L. V. & Richards, R. I. The pathogenic agent in Drosophila models of ‘polyglutamine’ diseases. Hum. Mol. Genet. 14, 1041–1048 (2005)

    Article  CAS  Google Scholar 

  17. Marsh, J. L. et al. Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum. Mol. Genet. 9, 13–25 (2000)

    Article  CAS  Google Scholar 

  18. 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 

  19. 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 

  20. 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 

  21. Goti, D. et al. A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J. Neurosci. 24, 10266–10279 (2004)

    Article  CAS  Google Scholar 

  22. Warrick, J. M. et al. Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol. Cell 18, 37–48 (2005)

    Article  CAS  Google Scholar 

  23. Jin, P. et al. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39, 739–747 (2003)

    Article  CAS  Google Scholar 

  24. Ranum, L. P. & Day, J. W. Pathogenic RNA repeats: an expanding role in genetic disease. Trends Genet. 20, 506–512 (2004)

    Article  CAS  Google Scholar 

  25. Tapscott, S. J. & Thornton, C. A. Reconstructing myotonic dystrophy. Science 293, 816–817 (2001)

    Article  CAS  Google Scholar 

  26. Cho, D. H. et al. Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol. Cell 20, 483–489 (2005)

    Article  CAS  Google Scholar 

  27. Moseley, M. L. et al. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nature Genet. 38, 758–769 (2006)

    Article  CAS  Google Scholar 

  28. Osherovich, L. Z. & Weissman, J. S. Multiple Gln/Asn-rich prion domains confer susceptibility to induction of the yeast [PSI(+)] prion. Cell 106, 183–194 (2001)

    Article  CAS  Google Scholar 

  29. Garcia-Casado, M. Z., Artero, R. D., Paricio, N., Terol, J. & Perez-Alonso, M. Generation of GAL4-responsive muscleblind constructs. Genesis 34, 111–114 (2002)

    Article  CAS  Google Scholar 

  30. Jung, J. & Bonini, N. CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease. Science 315, 1857–1859 (2007)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Cashmore, D. Lessing and R. Pittman for comments, J. Weissman, C. Thornton, M. Baylies, R. Artero and the Developmental Studies Hybridoma Bank (supported by the National Institute of Child Health and Human Development and the University of Iowa) for reagents. These studies were supported by the National Institute of Neurological Disorders and Stroke (to N.M.B.). N.M.B. is an Investigator of the Howard Hughes Medical Institute.

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  1. Ling-Bo Li

    Present address: Present address: Department of Biochemistry, University of Utah, Salt Lake City, Utah 84112-5650, USA.,

Authors and Affiliations

  1. Department of Biology,,

    Ling-Bo Li, Zhenming Yu, Xiuyin Teng & Nancy M. Bonini

  2. Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6018, USA,

    Zhenming Yu, Xiuyin Teng & Nancy M. Bonini

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  1. Ling-Bo Li
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Correspondence to Nancy M. Bonini.

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Supplementary information

The file contains Supplementary Tables S1-S2, Supplementary Figures S1-S16 with Legends and additional references. (PDF 1054 kb)

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Li, LB., Yu, Z., Teng, X. et al. RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453, 1107–1111 (2008). https://doi.org/10.1038/nature06909

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