Thomas, Oliver Lloyd; (2025) The impact of ribosomal mutations on translation, proteostasis, and ageing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The accurate translation of mRNA to a polypeptide chain is necessary for the synthesis of properly folded proteins, contributing to the maintenance of proteostasis. Decreases in the accuracy of this process therefore incur the risk of dysregulated proteostasis and chronic proteotoxic stress, contributing towards the aetiology of many age-related diseases. Mutations of the prokaryotic ribosomal protein RpsL have long been shown to induce resistance to the error causing antibiotic streptomycin by presenting hyper-accuracy phenotypes. One such mutation; K42R, has since been introduced into the equivalent eukaryotic protein; RPS23, of D. melanogaster. Here, this also leads to a hyper-accuracy phenotype whilst also improving proteostasis and extending lifespan. Intriguingly, this amino acid variation has also been identified as an evolved alteration in hyperthermophilic archaea, where it is hypothesised to aid in survival at high temperatures by improving accuracy. The aim of this thesis was to interrogate additional mutations of RPS23 identified from streptomycin-resistant bacteria and hyperthermophilic archaea, to assess whether commonalities can be identified between their effects on translational accuracy, proteostasis, and lifespan. Using fission yeast, the impact of these mutations on lifespan and translational accuracy were assessed. Lifespan was extended by the introduction of all but one of the mutations; however, translational accuracy was reduced and the two were not correlated. The impact of mutations on proteostasis was then assessed by inhibiting key parts of the proteostasis network. Here, improvements in cytosolic proteostasis were observed that; unlike translational accuracy, were correlated with lifespan. Finally, alternative changes in translation known to improve lifespan were assessed in a Drosophila derived cell line. This showed that lifespan-extending inhibition of an initiation factor increased cap-independent translation initiation, whilst decreasing translational accuracy. Together these findings have demonstrated that beneficial mutations of RPS23 improve proteostasis and extend lifespan through a more complex mechanisms than improved accuracy alone.

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