ArticleNucleic acids research2021
Formation and persistence of polyglutamine aggregates in mistranslating cells.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 32 citations in OpenAlex.
- Mistranslation from an endogenous tRNA variant in human pan-genome cell lines.Nucleic acids research · 2026Article
- Article
- Mistranslating tRNA variants impact the proteome and phosphoproteome of Saccharomyces cerevisiae.G3 (Bethesda, Md.) · 2026Article
- Mistranslating tRNA variants impact the proteome and phosphoproteome ofbioRxiv : the preprint server for biology · 2025Article
- High-fidelity and differential nonsense suppression in live cells and a frontotemporal dementia allele with human transfer RNAs.Nucleic acids research · 2025Article
- Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.The FEBS journal · 2025Review
- Natural human tRNARNA (New York, N.Y.) · 2025Article
- Specific branches of the proteostasis network regulate the toxicity associated with mistranslation.Nucleic acids research · 2025Article
- Glutamine missense suppressor transfer RNAs inhibit polyglutamine aggregation.Molecular therapy. Nucleic acids · 2025Article
- Mistranslating tRNA variants have anticodon- and sex-specific impacts on Drosophila melanogaster.G3 (Bethesda, Md.) · 2024Article
- Impact of tRNA-induced proline-to-serine mistranslation on the transcriptome of Drosophila melanogaster.G3 (Bethesda, Md.) · 2024Article
- Mechanisms and Delivery of tRNA Therapeutics.Chemical reviews · 2024Review
- Mistranslating tRNA variants have anticodon- and sex-specific impacts onbioRxiv : the preprint server for biology · 2024Article
- Impact of tRNA-induced proline-to-serine mistranslation on the transcriptome ofbioRxiv : the preprint server for biology · 2024Article
- Article
- Genome-wide screening reveals metabolic regulation of stop-codon readthrough by cyclic AMP.Nucleic acids research · 2023Article
- Article
- Mistranslation of the genetic code by a new family of bacterial transfer RNAs.The Journal of biological chemistry · 2023Article
- Review
- Perseverance of protein homeostasis despite mistranslation of glycine codons with alanine.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
In neurodegenerative diseases, including pathologies with well-known causative alleles, genetic factors that modify severity or age of onset are not entirely understood. We recently documented the unexpected prevalence of transfer RNA (tRNA) mutants in the human population, including variants that cause amino acid mis-incorporation. We hypothesized that a mistranslating tRNA will exacerbate toxicity and modify the molecular pathology of Huntington's disease-causing alleles. We characterized a tRNAPro mutant that mistranslates proline codons with alanine, and tRNASer mutants, including a tRNASerAGA G35A variant with a phenylalanine anticodon (tRNASerAAA) found in ∼2% of the population. The tRNAPro mutant caused synthetic toxicity with a deleterious huntingtin poly-glutamine (polyQ) allele in neuronal cells. The tRNASerAAA variant showed synthetic toxicity with proteasome inhibition but did not enhance toxicity of the huntingtin allele. Cells mistranslating phenylalanine or proline codons with serine had significantly reduced rates of protein synthesis. Mistranslating cells were slow but effective in forming insoluble polyQ aggregates, defective in protein and aggregate degradation, and resistant to the neuroprotective integrated stress response inhibitor (ISRIB). Our findings identify mistranslating tRNA variants as genetic factors that slow protein aggregation kinetics, inhibit aggregate clearance, and increase drug resistance in cellular models of neurodegenerative disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.