Transfer RNA Missense Suppressors in Nature and Disease

Rasangi Tennakoon, Western University

Abstract

Transfer RNAs (tRNAs) serve as the bridge between the genome and proteome by recognizing the three-nucleotide codons in messenger RNAs and incorporating the correct amino acids into growing polypeptide chains. My goal was to assess the impact of human missense suppressor tRNAs that cause mistranslation, and their therapeutic potential in neurodegenerative disease. First, I created synthetic tRNA^Ala and tRNA^Ser anticodon mutants that mis-incorporate alanine or serine in expanded polyglutamine tracts in cellular models of Huntington’s disease. I found that tRNA^Ala_CUG significantly reduced disease-causing protein aggregates without inducing cytotoxicity. Then, I characterized three tRNA^Ala genes with anticodon variants that occur naturally in the human population. Expression of each variant in cells caused misincorporation of alanine at different codons and led to significant defects in protein production and cell proliferation. These findings demonstrate that mistranslation of alanine by tRNA missense suppressors can differentially affect protein synthesis, aggregation, and growth of human cells.