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Aberrant tRNA function exacerbates TDP-43 misfolding and toxicity in cellular models of ALS

Principal Investigator:
  • Donovan McDonald, University of Western Ontario
  • ALS Society of Canada

Project Overview

Aberrant tRNA processing and function has the capacity to exacerbate misfolding of ALS-associated proteins and the ensuing toxicity. tRNAs mainly function to recruit amino acids to ribosomes, allowing faithful translation of mRNA molecules. Metabolites of processed tRNAs also function in cellular stress responses, such as inducing stress granule formation. The human population contains high incidences of tRNA variants that cause amino acid mis-incorporation, leading to mistranslation. Furthermore, mutations in tRNA modifying genes also induce mistranslation, causing protein misfolding. In addition, mutations in the gene encoding angiogenin, an enzyme that cleaves tRNAs into fragments, cause familial forms of ALS. Aberrant tRNA function and processing has never been investigated in the context of ALS. Yet, our findings and those of our collaborators indicate several mechanisms through which tRNAs regulate misfolding of proteins in ALS. I will elucidate previously unexplored mechanisms by which aberrant tRNA function regulates the misfolding and ensuing toxicity of ALS-associated proteins, focusing on TDP-43. To this end, I will leverage results from genetically and biochemically tractable yeast models and suitable neuronal cell models of ALS.  My research will help to establish aberrant tRNA metabolism as risk factors, biomarkers, and possibly therapeutic targets for the diagnosis and treatment of ALS.