Formation and persistence of polyglutamine aggregates in mistranslating cells

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 tRNA Pro mutant that mistranslates proline codons with alanine, and tRNA Ser mutants, including a tRNA Ser AGA G35A variant with a phenylalanine anticodon (tRNA Ser AAA ) found in ∼2% of the population. The tRNA Pro mutant caused synthetic toxicity with a deleterious huntingtin poly-glutamine (polyQ) allele in neuronal cells. The tRNA Ser AAA 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.

Increase in Ribosomal Fidelity Benefits Salmonella upon Bile Salt Exposure

“…Translational errors affect protein misfolding and aggregation [ 13 , 36 ]. Interestingly, it has also been well established that bile salts cause misfolding and the denaturation of proteins [ 34 , 37 ].…”

“…Although cells have evolved several quality control mechanisms to minimize errors [ 3 , 4 , 5 , 6 ], mistranslation still occurs to some extent because of genetic mutations [ 7 , 8 ] and external stresses, such as heat [ 9 ] and antibiotics [ 10 ]. Under severe mistranslation stress, this can result in the accumulation and aggregation of abnormal proteins that ultimately lead to growth inhibition and cell death [ 11 , 12 , 13 ]. Therefore, it is commonly thought that mistranslation is detrimental to the cell.…”

Alpiniae oxyphyllae fructus possesses neuroprotective effects on H2O2 stimulated PC12 cells via regulation of the PI3K/Akt signaling Pathway

“…In order to verify whether the hypothesis proposed in the above network analysis is correct, we then conducted corresponding in vitro experiments to further verify. PC12 is a rat-derived cell line with similar characteristics to neurons, which can mimic the physiological and pathological processes of nerve cells ( Lant et al, 2021 ; Chen et al, 2022 ). In addition, H 2 O 2 is a small molecule compound with high cell membrane permeability.…”

Genome-wide screening reveals metabolic regulation of translational fidelity

“…The amino acid misincorporation rate at sense codons is approximately 10 -4 to 10 -3 and the frequency of stop-codon readthrough is even higher at 10 -3 to 10 -2 (8)(9)(10)(11)(12). It is important to note that such error rates are not fixed and can fluctuate due to mutations, mRNA context, and environmental changes (2,(13)(14)(15)(16)(17). Mutations in aaRSs and tRNAs may lead to the production of misacylated tRNAs, which are used by the ribosome to make erroneous proteins (6,(18)(19)(20)(21)(22).…”

“…Mutations in aaRSs and tRNAs may lead to the production of misacylated tRNAs, which are used by the ribosome to make erroneous proteins (6,(18)(19)(20)(21)(22). Recent studies suggest that some tRNA variants in human populations lead to increased translational errors and could function as disease modifiers (17,23). Similarly, mutations in ribosomal proteins and RNAs can also affect the decoding accuracy and cause amino acid misincorporation, stop-codon readthrough, and frameshift (11,24,25).…”