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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., & Yoshimori, T. (2000) · The EMBO Journal · doi:10.1093/emboj/19.21.5720 · Cited by 6,605
Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S. W., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81369-0 · Cited by 3,073
Davies, S. W., Turmaine, M., Cozens, B. A., DiFiglia, M., Sharp, A. H., Ross, C. A., Scherzinger, E., Wanker, E. E., Mangiarini, L., & Bates, G. P. (1997) · Cell · doi:10.1016/s0092-8674(00)80513-9 · Cited by 2,188
TOR, a Central Controller of Cell Growth
Schmelzle, T., & Hall, M. N. (2000) · Cell · doi:10.1016/s0092-8674(00)00117-3 · Cited by 1,914
Saudou, F., Finkbeiner, S. M., Devys, D., & Greenberg, M. E. (1998) · Cell · doi:10.1016/s0092-8674(00)81782-1 · Cited by 1,598
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
Steffan, J. S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y.-Z., Greenwald, M., et al. (2001) · Nature · doi:10.1038/35099568 · Cited by 1,228
Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy
Ravikumar, B. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.9.1107 · Cited by 1,099
Self-citationMammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E
Fingar, D. C., Salama, S., Tsou, C., Harlow, E., & Blenis, J. (2002) · Genes & Development · doi:10.1101/gad.995802 · Cited by 1,093
Kim, D., Sarbassov, D. D., Ali, S. M., Latek, R. R., Guntur, K., Erdjument‐Bromage, H., Tempst, P., & Sabatini, D. M. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00114-x · Cited by 992
Nuclear and Neuropil Aggregates in Huntington’s Disease: Relationship to Neuropathology
Gutekunst, C.-A., Li, S.-H., Yi, H., Mulroy, J. S., Kuemmerle, S., Jones, R., Rye, D., Ferrante, R. J., Hersch, S. M., & Li, X.-J. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-07-02522.1999 · Cited by 914
Autophagosome Formation in Mammalian Cells.
Mizushima, N., Ohsumi, Y., & Yoshimori, T. (2002) · Cell Structure and Function · doi:10.1247/csf.27.421 · Cited by 897
Hockly, E., Richon, V. M., Woodman, B., Smith, D. L., Zhou, X., Rosa, E., Sathasivam, K., Ghazi‐Noori, S., Mahal, A., Lowden, P. A. S., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0437870100 · Cited by 847
Rogers, D. C., Fisher, E. M. C., Brown, S. D. M., Peters, J., Hunter, A. J., & Martin, J. E. (1997) · Mammalian Genome · doi:10.1007/s003359900551 · Cited by 795
Schilling, G. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.3.397 · Cited by 772
Tang, S. J., Reis, G., Kang, H., Gingras, A.-C., Sonenberg, N., & Schuman, E. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012605299 · Cited by 734
Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease
Dunah, A. W., Jeong, H., Griffin, A. M., Kim, Y., Standaert, D. G., Hersch, S. M., Mouradian, M. M., Young, A. B., Tanese, N., & Krainc, D. (2002) · Science · doi:10.1126/science.1072613 · Cited by 708
Waelter, S., Boeddrich, A., Lurz, R., Scherzinger, E., Lüder, G., Lehrach, H., & Wanker, E. E. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.5.1393 · Cited by 637
Regulation of cellular growth by the Drosophila target of rapamycin dTORPreprint
Zhang, H., Stallock, J. P., Ng, J., Reinhard, C., & Neufeld, T. P. (2000) · Genes & Development · doi:10.1101/gad.835000 · Cited by 624
Jackson, G. R., Salecker, I., Dong, X., Yao, X., Arnheim, N., Faber, P. W., MacDonald, M. E., & Zipursky, S. L. (1998) · Neuron · doi:10.1016/s0896-6273(00)80573-5 · Cited by 535
Huntingtin Expression Stimulates Endosomal–Lysosomal Activity, Endosome Tubulation, and Autophagy
Kegel, K. B., Kim, M., Sapp, E., McIntyre, C., Castaño, J. G., Aronin, N., & DiFiglia, M. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-19-07268.2000 · Cited by 533
Rheb fills a GAP between TSC and TOR
Manning, B. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.09.003 · Cited by 483
Murphy, K. P. S. J., Carter, R. J., Lione, L. A., Mangiarini, L., Mahal, A., Bates, G. P., Dunnett, S. B., & Morton, A. J. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-13-05115.2000 · Cited by 398
Therapeutic Effects of Coenzyme Q10and Remacemide in Transgenic Mouse Models of Huntington's Disease
Ferrante, R. J., Andreassen, O. A., Dedeoglu, A., Ferrante, K. L., Jenkins, B. G., Hersch, S. M., & Beal, M. F. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01592.2002 · Cited by 391
Lione, L. A., Carter, R. J., Hunt, M. J., Bates, G. P., Morton, A. J., & Dunnett, S. B. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-23-10428.1999 · Cited by 388
Wyttenbach, A., Carmichael, J., Swartz, J., Furlong, R. A., Narain, Y., Rankin, J., & Rubinsztein, D. C. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.6.2898 · Cited by 362
Self-citationHuntington aggregates may not predict neuronal death in Huntington's disease.
Kuemmerle, S., Gutekunst, C., Klein, A., Li, X. J., Li, S. H., Beal, M. F., Hersch, S. M., & Ferrante, R. J. (1999) · PubMed · Cited by 362
Huntingtin localization in brains of normal and Huntington's disease patients
Sapp, E., Schwarz, C., Chase, K. O., Bhide, P. G., Young, A. B., Penney, J. B., Vonsattel, J. P., D, N. A. M., & DiFiglia, M. (1997) · Annals of Neurology · doi:10.1002/ana.410420411 · Cited by 350
Rapamycins: Mechanisms of Action and Cellular Resistance
Huang, S., Bjornsti, M., & Houghton, P. J. (2003) · Cancer Biology & Therapy · doi:10.4161/cbt.2.3.360 · Cited by 288
Formation of Polyglutamine Inclusions in Non-CNS Tissue
Sathasivam, K., Hobbs, C., Turmaine, M., Mangiarini, L., Mahal, A., Bertaux, F., Wanker, E. E., Doherty, P., Davies, S. W., & Bates, G. P. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.5.813 · Cited by 286
Lessons from animal models of Huntington's disease
Rubinsztein, D. C. (2002) · Trends in Genetics · doi:10.1016/s0168-9525(01)02625-7 · Cited by 281
Self-citationWyttenbach, A. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.17.1829 · Cited by 274
mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo
Kwon, C.-H., Zhu, X., Zhang, J., & Baker, S. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2132711100 · Cited by 235
Les phénomènes de pseudopupille dans l'œil composé deDrosophila
Franceschini, N. H., & Kirschfeld, K. (1971) · Kybernetik · doi:10.1007/bf02215177 · Cited by 233
Yoo, S.-Y., Pennesi, M. E., Weeber, E. J., Xu, B., Atkinson, R., Chen, S., Armstrong, D. L., Wu, S. M.-S., Sweatt, J. D., & Zoghbi, H. Y. (2003) · Neuron · doi:10.1016/s0896-6273(02)01190-x · Cited by 233
Impaired Synaptic Plasticity in Mice Carrying the Huntington's Disease Mutation
Usdin, M., Shelbourne, P., Myers, R., & Madison, D. V. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.5.839 · Cited by 230
Kim, J. E., & Chen, J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.011511898 · Cited by 198
A note on grammars with regular restrictions.
Král, J. (1973) · Czech digital mathematics library · Cited by 151
Mechanisms of resistance to rapamycins
Huang, S., & Houghton, P. J. (2001) · Drug Resistance Updates · doi:10.1054/drup.2002.0227 · Cited by 143
Polyglutamines Placed into Context
Spada, A. R. L., & Taylor, J. P. (2003) · Neuron · doi:10.1016/s0896-6273(03)00328-3 · Cited by 142
The Role of Protein Composition in Specifying Nuclear Inclusion Formation in Polyglutamine Disease
Chai, Y., Wu, L., Griffin, J. D., & Paulson, H. L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106575200 · Cited by 116
Control of Translation by the Target of Rapamycin Proteins
Gingras, A., Raught, B., & Sonenberg, N. (2001) · Progress in molecular and subcellular biology · doi:10.1007/978-3-662-09889-9_6 · Cited by 99
Inhibition of cellular growth and proliferation by dTOR overexpression in Drosophila
Hennig, K. M., & Neufeld, T. P. (2002) · genesis · doi:10.1002/gene.10139 · Cited by 97
Serkova, N. J., Jacobsen, W., Niemann, C. U., Litt, L. L., Benet, L. Z., Leibfritz, D., & Christians, U. (2001) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704142 · Cited by 83
Schwab, M., Kim, S. H., Terada, N., Edfjall, C., Kozma, S., Thomas, G., & Maller, J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.4.2485 · Cited by 48
Elit, L. M. (2002) · PubMed · Cited by 43
Prevention of neointimal proliferation by immunosuppression in synthetic vascular grafts
Walpoth, B. H., Pavlicek, M., Çelik, B., Nicolaus, B., Schaffner, T. J., Althaus, U., Hess, O. M., Carrel, T. P., & Morris, R. E. (2001) · European Journal of Cardio-Thoracic Surgery · doi:10.1016/s1010-7940(01)00582-6 · Cited by 38
Dose-dependent pharmacokinetics of rapamycin-28-N,N-dimethylglycinate in the mouse
Supko, J. G., & Malspeis, L. (1994) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00685908 · Cited by 27
Flagged first, then by citations
Cited by
Sorted by citations
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review