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RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia

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

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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Figure 1: Silencing ataxin-1.
Figure 2: AAV vectors for shRNA expression in vivo.
Figure 3: SCA1 neuropathology is improved by shRNAs directed to ataxin-1.
Figure 4: RNAi reduces intranuclear inclusions in transduced cells.

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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

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  1. Haibin Xia
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Correspondence to Beverly 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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