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- W3209383543 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." @default.
- W3209383543 created "2021-11-08" @default.
- W3209383543 creator A5036745772 @default.
- W3209383543 creator A5057540389 @default.
- W3209383543 creator A5070665448 @default.
- W3209383543 creator A5082950009 @default.
- W3209383543 date "2021-10-28" @default.
- W3209383543 modified "2023-10-03" @default.
- W3209383543 title "Formation and persistence of polyglutamine aggregates in mistranslating cells" @default.
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- W3209383543 doi "https://doi.org/10.1093/nar/gkab898" @default.
- W3209383543 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8599886" @default.
- W3209383543 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34718744" @default.
- W3209383543 hasPublicationYear "2021" @default.
- W3209383543 type Work @default.