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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 \u223c2% 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.<\/jats:p>","DOI":"10.1093\/nar\/gkab898","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T03:12:39Z","timestamp":1632193959000},"page":"11883-11899","source":"Crossref","is-referenced-by-count":32,"title":["Formation and persistence of polyglutamine aggregates in mistranslating cells"],"prefix":"10.1093","volume":"49","author":[{"given":"Jeremy T","family":"Lant","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi","family":"Kiri","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin L","family":"Duennwald","sequence":"additional","affiliation":[{"name":"Department of Anatomy & Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9500-8640","authenticated-orcid":false,"given":"Patrick","family":"O\u2019Donoghue","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada"},{"name":"Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"2021120105595713700_B1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/0022-2836(68)90392-6","article-title":"The origin of the genetic code","volume":"38","author":"Crick","year":"1968","journal-title":"J. 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