The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease
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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“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
In the citing paper
“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]
Citations
Cites
LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
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α-Synuclein Is Degraded by Both Autophagy and the Proteasome
Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N., & Rubinsztein, D. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300227200 · Cited by 1,429
Self-citationHistone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
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Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy
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Self-citationMammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E
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Autophagy fights disease through cellular self-digestion
Mizushima, N., Levine, B., Cuervo, A. M., & Klionsky, D. J. (2008) · Nature · doi:10.1038/nature06639 · Cited by 6,452
Methods in Mammalian Autophagy Research
Mizushima, N., Yoshimori, T., & Levine, B. (2010) · Cell · doi:10.1016/j.cell.2010.01.028 · Cited by 4,497
Autophagy: process and functionPreprint
Mizushima, N. (2007) · Genes & Development · doi:10.1101/gad.1599207 · Cited by 4,104
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941
Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006) · Nature · doi:10.1038/nature04724 · Cited by 3,882
Metadata
- 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
- Licence
- www.springer.com/tdm (tdm)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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