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Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease

Nature Genetics volume 36, pages 585–595 (2004)Cite this article

Abstract

Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.

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Figure 1: mTOR is sequestered in mutant huntingtin aggregates in cell models, transgenic mice and human brain.
Figure 2: Reduced levels of soluble mTOR and impaired mTOR-dependent phosphorylation of its substrates S6K1 and 4E-BP1 in Huntington disease.
Figure 3: Impaired phosphorylation of ribosomal protein S6 and dysregulation of TOP-dependent translation.
Figure 4: Polyglutamine expansion induces autophagy.
Figure 5: mTOR activity regulates polyglutamine toxicity in cells and flies.
Figure 6: CCI-779 improves behavior and motor performance in a mouse model of Huntington disease16.
Figure 7: CCI-779 reduces weight gain in mice.
Figure 8: CCI-779 reduces mTOR activity and aggregate load in mice expressing mutant huntingtin.

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Acknowledgements

We thank Wyeth Pharmaceuticals for the gift of CCI-779; G. Jackson for the fly model of Huntington disease; E. J. L. Maller and J. Chen for control and TOP luciferase vectors; N. Khan for brain samples from humans with Huntington disease and controls; A. Tobin for Gln25 and Gln103 constructs; H. Zoghbi for the ataxin constructs; W. J. Strittmatter for Gln19 and Gln81 constructs; K. L. Guan for rheb and FLAG-4E-BP1 constructs; T. Yoshimori for the antibody to LC3; A. Acevedo and E. Terrenoire for help with mouse brain samples; R. Padinjat for help with pseudopupil illumination; and M. Bobrow, D. Clayton and J. D. Cooper for helpful suggestions. We acknowledge funding from the Commonwealth Scholarship Commission for Ph.D. scholarship (B.R.), the Wellcome Trust for a Senior Clinical Research Fellowship (D.C.R.), a Senior Fellowship in Basic Biomedical Science (R.D.), a Prize Studentship (Z.B.), The Cambridge Overseas Trust (Z.B.), The Biotechnology and Biological Sciences Research Council for a Career Development Award (C.J.O.) and a Medical Research Council programme grant to D.C.R and S. Brown.

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  1. Brinda Ravikumar and Coralie Vacher: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK

    Brinda Ravikumar, Coralie Vacher, Zdenek Berger, Janet E Davies, Shouqing Luo, Lourdes G Oroz & David C Rubinsztein

  2. Department of Genetics, Cambridge University, Cambridge, CB2 3EH, UK

    Zdenek Berger & Cahir J O'Kane

  3. Division of Neuropathology, Institute of Neurology, University College London, London, UK

    Francesco Scaravilli

  4. Department of Public Health, Cancer Research U.K., Genetic Epidemiology Unit, University of Cambridge, Cambridge, UK

    Douglas F Easton

  5. Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, UK

    Rainer Duden

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  1. Brinda Ravikumar
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Correspondence to David C Rubinsztein.

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Ravikumar, B., Vacher, C., Berger, Z. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36, 585–595 (2004). https://doi.org/10.1038/ng1362

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