Induction of autophagy with catalytic mTOR inhibitors reduces huntingtin aggregates in a neuronal cell model
Abstract
J. Neurochem. (2011) 119 , 398–407. Huntington’s disease is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. This expansion produces a mutant form of the huntingtin protein, which contains an elongated polyglutamine stretch at its amino‐terminus. Mutant huntingtin may adopt an aberrant, aggregation‐prone conformation predicted to start the pathogenic process leading to neuronal dysfunction and cell death. Thus, strategies reducing mutant huntingtin may lead to disease‐modifying therapies. We investigated the mechanisms and molecular targets regulating huntingtin degradation in a neuronal cell model. We first found that mutant and wild‐type huntingtin displayed strikingly diverse turn‐over kinetics and sensitivity to proteasome inhibition. Then, we show that autophagy induction led to accelerate degradation of mutant huntingtin aggregates. In our neuronal cell model, allosteric inhibition of mTORC1 by everolimus, a rapamycin analogue, did not induce autophagy or affect aggregate degradation. In contrast, this occurred in the presence of catalytic inhibitors of both mTOR complexes mTORC1 and mTORC2. Our data demonstrate the existence of an mTOR‐dependent but everolimus‐independent mechanism regulating autophagy and huntingtin‐aggregate degradation in cells of neuronal origin.
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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 [385]
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- Authors
- Roscic, A., Baldo, B., Crochemore, C., Marcellin, D., & Paganetti, P.
- Affiliations
- Novartis (Switzerland) (CH)
- ORCID
- Paganetti, Paolo
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2011-09-20
- Volume
- 119
- Issue
- 2
- Pages
- 398-407
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1904622810
- Cited by
- 92
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 9 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 9 · 2015: 8 · 2014: 9 · 2013: 12 · 2012: 11
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Huntington's disease, mutant huntingtin, huntingtin aggregates, autophagy, mTOR inhibitors, mTORC1, mTORC2, everolimus, proteasome inhibition, protein degradation, polyglutamine, neuronal cell model, disease-modifying therapy
- MeSH terms
- Everolimus, Huntingtin Protein, Mechanistic Target of Rapamycin Complex 1, Autophagy, Cells, Cultured, Exons, Humans, Immunoassay, Immunosuppressive Agents, Kinetics, Models, Neurological, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Proteins, RNA, Messenger, Blotting, Western, Sirolimus, Multiprotein Complexes, TOR Serine-Threonine Kinases
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