Mechanistic Target of Rapamycin Complex 1 (mTORC1) regulates cell growth and proliferation by balancing anabolic and catabolic pathways. Dysregulation of mTORC1 signaling is implicated in numerous pathologies. We previously reported that mitochondrial threonyl-tRNA synthetase (TARS2), responsible for charging threonine (Thr) onto its cognate tRNA, modulates the mTORC1 pathway (Kim et al., Mol. Cell, 2021). Furthermore, patients harboring biallelic mutations in the TARS2 gene exhibit neurodevelopmental phenotypes (Accogli et al., Genet. Med., 2023), demonstrating the profound clinical relevance. Our goal is to elucidate the molecular mechanisms and functional significance of the Thr-TARS2-mTORC1 axis in human health and disease, particularly in neurodevelopmental disorders.

Protein synthesis is critical for maintaining essential brain functions, such as learning and memory. mRNA translation initiation is the rate-limiting step of protein synthesis, orchestrated by eukaryotic initiation factors including the eIF2-GTP-Met:tRNAi ternary complex and the eIF4F complex (composed of eIF4E, eIF4A, and eIF4G). We previously demonstrated that aberrant translational control of specific mRNA subsets impairs mitochondrial energy metabolism, neurodevelopment, and cognitive function in mice (Kim et al., Proc. Natl. Acad. Sci. U. S. A., 2023). To further elucidate these mechanisms, we investigate the role of de novo protein synthesis across neurodevelopment, metabolism, and cognition, and how its dysregulation contributes to the pathogenesis of brain disorders.

The gut-brain axis, a complex, bidirectional communication network between the central nervous system and the gastrointestinal tract, has been increasingly implicated in human health and disease, particularly neuropsychiatric disorders. While the gut microbiota is known to influence critical brain functions and mental health via microbial metabolites, such as short-chain fatty acids (SCFAs), the underlying molecular mechanisms remain poorly understood. Focusing on the mTOR and integrated stress response (ISR) pathways, our lab investigates the regulatory effects of the gut microbiota on the brain translatome in a chronic unpredictable mild stress (CUMS)-induced depression model. Ultimately, we aim to translate these mechanistic insights into innovative, microbiota-targeted strategies for the prevention, diagnosis, and treatment of depression and various neurological disorders.