Cited by 2,347Genetic Neurodegenerative DiseasesAutophagy in Disease and TherapyGenetics and Neurodevelopmental Disorders

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

Ravikumar, Brinda, Vacher, Coralie, Berger, Zdenek, Davies, Janet E, Luo, Shouqing, Oroz, Lourdes G, Scaravilli, Francesco, Easton, Douglas F +3 more·2004·Nature Genetics

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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Crossref · 10.1038/ng1362

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49 of 49 references verified0 citation errors · 0 not checkable

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  • Genetic and pharmacological restoration of autophagic/mitophagic clearance in animal models of neurodegenerative diseases ameliorates disease-defining pathologies and behavioral deficits.

    “Genetic and pharmacological restorations of autophagic/mitophagic clearance in animal models of these diseases ameliorate disease-defining pathologies and behavioral deficits (Fang et al., 2019; Ravikumar et al., 2004; Sliter et al., 2018).”

    From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Ravikumar et al., 2004

  • Rapamycin has been shown to reduce toxic-aggregate formation and disease progression by increasing autophagy in mouse and fly models of Huntington's disease and tauopathy.

    “For example, rapa mycin has been shown to reduce toxic-aggregate formation and disease progression by increasing autophagy in mouse and fly models of Huntington’s disease and tauopathy (59).”

    From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [59]

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Authors
Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., Scaravilli, F., Easton, D. F., Duden, R., O'Kane, C. J., & Rubinsztein, D. C.
Affiliations
  • University of Cambridge (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • Addenbrooke's Hospital (GB)
Corresponding author
Rubinsztein, David C
Venue
Nature Genetics
Published
2004-05-16
Volume
36
Issue
6
Pages
585-595
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2111567059
Cited by
2,347
References
49
Citations by year
2026: 39 · 2025: 43 · 2024: 56 · 2023: 61 · 2022: 94 · 2021: 113 · 2020: 101 · 2019: 110 · 2018: 114 · 2017: 94 · 2016: 126 · 2015: 145 · 2014: 148 · 2013: 153 · 2012: 159
FWCI
29.14
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust
  • Commonwealth Scholarship Commission
  • Cambridge Overseas Trust
  • Directorate for Biological Sciences
  • Medical Research Council
  • Biotechnology and Biological Sciences Research Council
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Huntington's disease, mTOR, autophagy, polyglutamine expansion, rapamycin, temsirolimus, mutant huntingtin, protein aggregation, neurodegeneration, kinase inhibition, therapeutic target
MeSH terms
Huntingtin Protein, Animals, Autophagy, Disease Models, Animal, Drosophila melanogaster, Female, Humans, Huntington Disease, Male, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Protein Kinases, Protein Biosynthesis, COS Cells, Sirolimus, Macromolecular Substances, Protein Kinase Inhibitors, Mice, TOR Serine-Threonine Kinases

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