Identification of novel therapeutic targets to modulate proteostasis in humans

Abstract

The average life expectancy of the world's population is increasing, as well as the incidence of age-related diseases (ARD), including cancer, neurodegenerative, and metabolic diseases. One of the most important features, transversal to aging and ARD, is the impairment of the proteome homeostasis network (proteostasis). This is often characterized by an abnormal accumulation of protein aggregates within cells, impaired protein synthesis, proteotoxic stress generation, and ultimately cellular dysfunction/death. However, the cellular and molecular mechanisms that drive the occurrence of these phenotypes are still under investigation. During protein synthesis, transfer RNAs (tRNAs) are responsible for delivering the amino acids to the growing polypeptide chain by matching their anticodons with the respective mRNA codons. To ensure their correct functionality, tRNAs need to undergo a panoply of different modifications catalyzed by tRNA-modifying enzymes. More recently, deregulation of specific tRNA-modifying enzymes and/or tRNA modifications have been reported in different ARD, but their significance for proteotoxic stress in the disease context is underexplored. Here, we show that knockdown of the tRNA-modifying enzyme, Elp3, in human cells, induces a decrease in the catalyzed tRNA modifications (ncm5U34, mcm5U34, and mcm5s2U34) and a consequent accumulation of protein aggregates, proteotoxic stress generation, and decreased protein synthesis rate. We also found that ELP3 expression is downregulated in Alzheimer’s and Huntington patients. Additional experiments are ongoing to dissect the role of Elp3 in neurodegenerative disorders. In summary, our work validates the tRNA-modifying enzymes as new players in the proteostasis network, constituting promising therapeutic targets to attenuate protein aggregation phenotypes observed in conformational disorders.