The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6/2 mouse model of Huntington's disease
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Background: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion within the huntingtin gene. Mutant huntingtin protein misfolds and accumulates within neurons where it mediates its toxic effects. Promoting mutant huntingtin clearance by activating macroautophagy is one approach for treating Huntington's disease (HD). In this study, we evaluated the mTOR kinase inhibitor and macroautophagy promoting drug everolimus in the R6/2 mouse model of HD. Results: Everolimus decreased phosphorylation of the mTOR target protein S6 kinase indicating brain penetration. However, everolimus did not activate brain macroautophagy as measured by LC3B Western blot analysis. Everolimus protected against early declines in motor performance; however, we found no evidence for neuroprotection as determined by brain pathology. In muscle but not brain, everolimus significantly decreased soluble mutant huntingtin levels. Conclusions: Our data suggests that beneficial behavioral effects of everolimus in R6/2 mice result primarily from effects on muscle. Even though everolimus significantly modulated its target brain S6 kinase, this did not decrease mutant huntingtin levels or provide neuroprotection.
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Selective MTORC1 inhibition via everolimus or modulation of MTOR- and AKT-independent pathways with 10-NCP are more successful in neurons.
“Alternative methods have proven more successful in neurons, however, including selective MTORC1 inhibition via everolimus [385–387], or modulation of MTOR- and AKT-independent pathways with 10-NCP, an N10-substituted derivative of the heterocyclic dye compound and antipsychotic analog phenoxazine [384].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [386]
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- Authors
- Fox, J. H., Connor, T., Chopra, V., Dorsey, K., Kama, J. A., Bleckmann, D., Betschart, C., Hoyer, D., Frentzel, S., DiFiglia, M., Paganetti, P., & Hersch, S. M.
- Affiliations
- University of Wyoming (US)
- Harvard University (US)
- Novartis (Switzerland) (CH)
- Corresponding author
- Hersch, Steven M
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2010-06-22
- Volume
- 5
- Issue
- 1
- Pages
- 26-26
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC2908080
- OpenAlex
- W2109645575
- Cited by
- 94
- References
- 38
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 5 · 2019: 10 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 8 · 2014: 12 · 2013: 8 · 2012: 9
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Novartis Institutes for BioMedical Research
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- everolimus, mTOR inhibitors, Huntington's disease, mutant huntingtin, macroautophagy, R6/2 mouse model, neuroprotection, brain penetration, muscle, LC3B, motor performance
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