Research

Demystifying "mRNA Translation"

Translation is a three-step process of initiation, elongation, and termination that decodes genetic information from mRNAs and synthesizes proteins required for various cellular processes. Translation initiation controlled by upstream signaling pathways determines whether and at what rate protein synthesis occurs. Dysregulation of translation initiation is closely associated with many human diseases, such as cancer and neurodevelopmental disorders.

We reported that mitochondrial protein TARS2 affects the mTORC1 signaling pathway involved in translation initiation (Kim et al., Mol. Cell, 2021) and that patients harboring biallelic TARS2 variants display neurodevelopmental phenotypes (Accogli et al., Genet. Med., 2023). We also showed that insufficient translational control of a subset of mRNAs leads to defects in mitochondrial energy metabolism, early neurodevelopment, and cognitive function (Kim et al., Proc. Natl. Acad. Sci. U. S. A., 2023).

Our long-term goal is to investigate how mRNA translation is controlled, which mRNAs are translationally regulated, and what the physiological consequences are under pathophysiological conditions. This will help us understand the biological basis of human diseases and develop novel therapeutic strategies. To this end, we utilize a variety of experimental techniques, including translatome profiling, in vitro primary neuron culture, mitochondrial metabolomics, stereotaxic surgery, fiber photometry, and mouse behavioral testing, as well as classical biochemistry, molecular and cell biology.

Threonine-TARS2-mTORC1 Pathway and Neurodevelopmental Disorders

Mechanistic Target of Rapamycin Complex 1 (mTORC1) controls cell growth and proliferation by modulating anabolic and catabolic pathways. Dysregulation of mTORC1 activity has been implicated in a variety of diseases. Amino acids are one of the well-known environmental cues in the mTORC1 pathway, and mitochondrial Threonyl-tRNA Synthetase (TARS2) is responsible for threonine-mediated mTORC1 activation. Mutations in Tars2 gene have been found in patients displaying neurodevelopmental phenotypes, demonstrating its clinical importance. Our goal is to elucidate the molecular mechanisms and significance of the threonine-TARS2-mTORC1 pathway in human health and disease.

Translational Control in Neurodevelopment, Metabolism, and Cognitive Function

Protein synthesis is required for maintaining normal brain function, including learning and memory. Initiation of mRNA translation mediated by the eukaryotic initiation factors - eIF2-GTP-Met:tRNAi ternary complex and eIF4F composed of the 5' m7G cap-binding protein eIF4E, the RNA helicase eIF4A, and the scaffold protein eIF4G - is the rate-limiting step of protein synthesis. Disruption of this process impairs mitochondrial energy metabolism, early neuronal morphogenesis, and long-term memory of adult mice; however, the target mRNAs involved in these defects remain elusive. We are studying the role of de novo protein synthesis in neurodevelopment, metabolism, and cognition using translatome profiling in combination with metabolomics and bioinformatics.

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