Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies
Abstract
The formation of intra-neuronal mutant protein aggregates is a characteristic of several human neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease (PD) and polyglutamine disorders, including Huntington's disease (HD). Autophagy is a major clearance pathway for the removal of mutant huntingtin associated with HD, and many other disease-causing, cytoplasmic, aggregate-prone proteins. Autophagy is negatively regulated by the mammalian target of rapamycin (mTOR) and can be induced in all mammalian cell types by the mTOR inhibitor rapamycin. It can also be induced by a recently described cyclical mTOR-independent pathway, which has multiple drug targets, involving links between Ca(2+)-calpain-G(salpha) and cAMP-Epac-PLC-epsilon-IP(3) signalling. Both pathways enhance the clearance of mutant huntingtin fragments and attenuate polyglutamine toxicity in cell and animal models. The protective effects of rapamycin in vivo are autophagy-dependent. In Drosophila models of various diseases, the benefits of rapamycin are lost when the expression of different autophagy genes is reduced, implicating that its effects are not mediated by autophagy-independent processes (like mild translation suppression). Also, the mTOR-independent autophagy enhancers have no effects on mutant protein clearance in autophagy-deficient cells. In this review, we describe various drugs and pathways inducing autophagy, which may be potential therapeutic approaches for HD and related conditions.
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Rapamycin selectively activates autophagy through inhibiting the mTOR pathway and can extend the lifespan of mice.
“Rapamycin selectively activates autophagy through inhibiting the mTOR pathway [60] and can extend the lifespan of mice [79].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [60]
In primary MEFs, rapamycin (100 nM) significantly increased the LC3-II:LC3-I ratio.
“We used rapamycin (100 nM), which selectively activates autophagy through inhibiting the mTOR pathway [60] to activate autophagy in primary MEFs (MEF PRI), significantly increasing the LC3-II: LC3-I ratio (Fig. 5C).”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [60]
Rapamycin (100 nM) selectively activates autophagy through inhibiting the mTOR pathway.
“We used rapamycin (100 nM), which selectively activates autophagy through inhibiting the mTOR pathway [60] to activate autophagy in primary MEFs (MEF PRI), significantly increasing the LC3-II: LC3-I ratio (Fig. 5C).”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [60]
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- Authors
- Sarkar, S., Ravikumar, B., Floto, R. A., & Rubinsztein, D. C.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Rubinsztein, D C
- Venue
- Cell Death & Differentiation
- Published
- 2008-07-18
- Volume
- 16
- Issue
- 1
- Pages
- 46-56
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- OpenAlex
- W2062686313
- Cited by
- 578
- References
- 80
- Citations by year
- 2026: 27 · 2025: 22 · 2024: 31 · 2023: 22 · 2022: 32 · 2021: 39 · 2020: 29 · 2019: 35 · 2018: 25 · 2017: 31 · 2016: 41 · 2015: 31 · 2014: 40 · 2013: 43 · 2012: 31
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust (064354)
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research
- Medical Research Council
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- rapamycin, mTOR-independent autophagy, autophagy inducers, Huntington's disease, protein aggregation, neurodegenerative diseases, Drosophila model, therapeutic target
- MeSH terms
- Huntingtin Protein, Animals, Antibiotics, Antineoplastic, Autophagy, Disease Models, Animal, Drosophila, Gene Expression Regulation, Humans, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Protein Kinases, Protein Biosynthesis, Signal Transduction, Neurodegenerative Diseases, Sirolimus, TOR Serine-Threonine Kinases
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