Rapamycin Inhibits Polyglutamine Aggregation Independently of Autophagy by Reducing Protein Synthesis
Abstract
Accumulation of misfolded proteins and protein assemblies is associated with neuronal dysfunction and death in several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease (HD). It is therefore critical to understand the molecular mechanisms of drugs that act on pathways that modulate misfolding and/or aggregation. It is noteworthy that the mammalian target of rapamycin inhibitor rapamycin or its analogs have been proposed as promising therapeutic compounds clearing toxic protein assemblies in these diseases via activation of autophagy. However, using a cellular model of HD, we found that rapamycin significantly decreased aggregation-prone polyglutamine (polyQ) and expanded huntingtin and its inclusion bodies (IB) in both autophagy-proficient and autophagy-deficient cells (by genetic knockout of the atg5 gene in mouse embryonic fibroblasts). This result suggests that rapamycin modulates the levels of misfolded polyQ proteins via pathways other than autophagy. We show that rapamycin reduces the amount of soluble polyQ protein via a modest inhibition of protein synthesis that in turn significantly reduces the formation of insoluble polyQ protein and IB formation. Hence, a modest reduction in huntingtin synthesis by rapamycin may lead to a substantial decrease in the probability of reaching the critical concentration required for a nucleation event and subsequent toxic polyQ aggregation. Thus, in addition to its beneficial effect proposed previou…
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In Huntington's disease, pharmacological inhibition of mTOR by rapamycin is neuroprotective and attributed to activation of 4E-BP1 and inhibition of protein synthesis.
“Similar to our findings in PD, in Huntington's disease, pharmacological inhibition of mTOR by rapamycin is neuroprotective and this effect is attributed to the activation of 4E-BP1 and inhibition of protein synthesis in Huntington's disease (31).”
From Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis (2022) · cites this paper as [31]
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- Authors
- King, M. A., Hands, S., Hafiz, F., Mizushima, N., Tolkovsky, A. M., & Wyttenbach, A.
- Affiliations
- University of Southampton (GB)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 73
- Issue
- 4
- Pages
- 1052-1063
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2149960670
- Cited by
- 120
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 8 · 2018: 4 · 2017: 8 · 2016: 3 · 2015: 9 · 2014: 6 · 2013: 4 · 2012: 11
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- rapamycin, polyglutamine aggregation, huntingtin, inclusion bodies, protein synthesis inhibition, neurodegenerative diseases, Huntington's disease, protein misfolding, nucleation
- MeSH terms
- Huntingtin Protein, Autophagy-Related Protein 5, Animals, Anti-Bacterial Agents, Autophagy, Cells, Cultured, Inclusion Bodies, Cycloheximide, Fibroblasts, Humans, Microtubule-Associated Proteins, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Recombinant Fusion Proteins, Sodium Dodecyl Sulfate, Solubility, Protein Biosynthesis, Vimentin, Gene Deletion, Sirolimus, Protein Structure, Quaternary, Protein Transport, Ubiquitin, Green Fluorescent Proteins, Mice
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