RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia (original) (raw)

• Article
• Published: 04 July 2004
• Qinwen Mao1,2 na1,
• Steven L Eliason1,2,
• Scott Q Harper1,2,
• Inês H Martins1,2,
• Harry T Orr3,4,
• Henry L Paulson5,
• Linda Yang6,
• Robert M Kotin6 &
• …
• Beverly L Davidson1,2,5,7

Nature Medicine volume 10, pages 816–820 (2004)Cite this article

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Abstract

The dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatable, neurodegenerative disorders. In inducible mouse models of SCA1 and Huntington disease, repression of mutant allele expression improves disease phenotypes. Thus, therapies designed to inhibit expression of the mutant gene would be beneficial. Here we evaluate the ability of RNA interference (RNAi) to inhibit polyglutamine-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1. Upon intracerebellar injection, recombinant adeno-associated virus (AAV) vectors expressing short hairpin RNAs profoundly improved motor coordination, restored cerebellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice. Our data demonstrate in vivo the potential use of RNAi as therapy for dominant neurodegenerative disease.

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References

1. Orr, H.T. et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat. Genet. 4, 221–226 (1993).
   Article CAS Google Scholar
2. Zoghbi, H.Y. & Orr, H.T. Spinocerebellar ataxia type 1. Semin. Cell Biol. 6, 29–35 (1995).
   Article CAS Google Scholar
3. Skinner, P.J. et al. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389, 971–234 (1997).
   Article CAS Google Scholar
4. Fernandez-Funez, P. et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106 (2000).
   Article CAS Google Scholar
5. 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
6. 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
7. 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
8. Chen, H.K. et al. Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113, 457–468 (2003).
   Article CAS Google Scholar
9. Cummings, C.J. et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in Sca1. Nat. Genet. 19, 148–154 (1998).
   Article CAS Google Scholar
10. Caplen, N.J. et al. Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference. Hum. Mol. Genet. 11, 175–184 (2002).
    Article CAS Google Scholar
11. Miller, V.M. et al. Allele-specific silencing of dominant disease genes. Proc. Natl. Acad. Sci. USA 100, 7195–7200 (2003).
    Article CAS Google Scholar
12. Xia, H., Mao, Q., Paulson, H.L. & Davidson, B.L. siRNA-mediated gene silencing in vitro and in vivo. Nat. Biotechnol. 20, 1006–1010 (2002).
    Article CAS Google Scholar
13. Davidson, B.L. & Paulson, H.L. Molecular medicine for the brain: silencing disease genes with RNA interference. Lancet Neurol. 3, 145–149 (2004).
    Article CAS Google Scholar
14. Pittman, R.N., Wang, S., DiBenedetto, A.J. & Mills, J.C. A system for characterizing cellular and molecular events in programmed neuronal cell death. J. Neurosci. 13, 3669–3680 (1993).
    Article CAS Google Scholar
15. Kawasaki, H. & Taira, K. Short hairpin type of dsRNAs that are controlled by tRHAVal promoter significantly induce RNAi-mediated gene silencing in the cytoplasm of human cells. Nucleic Acids Res. 31, 700–707 (2003).
    Article CAS Google Scholar
16. Clark, H.B. et al. Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations. J. Neurosci. 17, 7385–7395 (1997).
    Article CAS Google Scholar
17. Alisky, J. et al. Transduction of murine cerebellar neurons with recombinant FIV and AAV5 vectors. Neuroreport 11, 2669–2673 (2000).
    Article CAS Google Scholar
18. Diener, H.-C. & Dichgans, J. Cerebellar and spinocerebellar gait disorders. in Clinical Disorders of Balance, Posture and Gait (eds. Bronstein, A.M., Brandt, T. & Woollacott, M.) 147–155 (Oxford University Press, 1996).
    Google Scholar
19. Stenoien, D.L., Mielke, M. & Mancini, M.A. Intranuclear ataxin1 inclusions contain both fast- and slow-exchanging components. Nat. Cell Biol. 4, 806–810 (2002).
    Article CAS Google Scholar
20. Chai, Y., Shao, J., Miller, V.M., Williams, A. & Paulson, H.L. Live-cell imaging reveals divergent intracellular dynamics of polyglutamine disease proteins and supports a sequestration model of pathogenesis. Proc. Natl. Acad. Sci. USA 99, 9310–9315 (2002).
    Article CAS Google Scholar
21. Khvorova, A., Reynolds, A. & Jayasena, S.D. Functional siRNAs and miRNAs exhibit strand bias. Cell 115, 505 (2003).
    Article CAS Google Scholar
22. Reynolds, A. et al. Rational siRNA design for RNA interference. Nat. Biotechnol. 22, 326–330 (2004).
    Article CAS Google Scholar
23. Urabe, M., Ding, C. & Kotin, R.M. Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum. Gene Ther. 13, 1935–1943 (2002).
    Article CAS Google Scholar
24. Miyagishi, M. & Taira, K. U6 promoter-driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat. Biotechnol. 20, 497–500 (2002).
    Article CAS Google Scholar
25. Williams, R.W. & Rakic, P. Three-dimensional counting: an accurate and direct method to estimate numbers of cells in sectioned material. J. Comp. Neurol. 278, 344–352 (1988).
    Article CAS Google Scholar

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Acknowledgements

We thank C. McLennan, J. Critchfield, S. Ries, N. Kiewiet and X. He for assistance. This work was supported by the National Institutes of Health (B.L.D., H.L.P. and H.T.O.), the Hereditary Disease Foundation (B.L.D., H.L.P. and S.Q.H.) and the Roy J. Carver Charitable Trust (B.L.D.).

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Author notes

1. Haibin Xia and Qinwen Mao: These authors contributed equally to this work.

Authors and Affiliations

1. Program in Gene Therapy, University of Iowa, Iowa City, Iowa, USA
   Haibin Xia, Qinwen Mao, Steven L Eliason, Scott Q Harper, Inês H Martins & Beverly L Davidson
2. Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
   Haibin Xia, Qinwen Mao, Steven L Eliason, Scott Q Harper, Inês H Martins & Beverly L Davidson
3. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
   Harry T Orr
4. Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota, USA
   Harry T Orr
5. Department of Neurology, University of Iowa, Iowa City, Iowa, USA
   Henry L Paulson & Beverly L Davidson
6. National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA
   Linda Yang & Robert M Kotin
7. Department of Physiology & Biophysics, University of Iowa, Iowa City, Iowa, USA
   Beverly L Davidson

Authors

1. Haibin Xia
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2. Qinwen Mao
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3. Steven L Eliason
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4. Scott Q Harper
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5. Inês H Martins
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6. Harry T Orr
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7. Henry L Paulson
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8. Linda Yang
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9. Robert M Kotin
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10. Beverly L Davidson
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Corresponding author

Correspondence toBeverly L Davidson.

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Competing interests

B.L.D. is a consultant for Sirna Therapeutics, Inc. and serves on the Scientific Advisory Board of Oxford BioMedica.

Supplementary information

Supplementary Fig. 1

Effects of shSCA1.F10mi and shSCA1.F11mi on ataxin-1 expression in mice cerebella. (PDF 125 kb)

Supplementary Fig. 2

Reductions in ataxin-1 inclusions in SCA1 mice requires transduction. (PDF 79 kb)

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Xia, H., Mao, Q., Eliason, S. et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.Nat Med 10, 816–820 (2004). https://doi.org/10.1038/nm1076

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• Received: 13 February 2004
• Accepted: 02 June 2004
• Published: 04 July 2004
• Issue Date: 01 August 2004
• DOI: https://doi.org/10.1038/nm1076

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