Research

Our long-term research goal is to understand 1) how controlled actions of genes, gene products, and relevant molecules shape animal behaviors and physiology; and 2) how their dysfunction leads to the development of neurological disorders. 

Given the versatility of genetic toolkits and the scalability of behavioral analyses, our lab had primarily employed Drosophila as an animal model to 1) identify new genes and neural circuits that control sleep-wake cycles; 2) demonstrate novel roles of the pure metabolic pathways in sleep regulation; 3) define a sleep-like state in brain-less Hydra vulgaris and propose a bold hypothesis on how sleep-regulatory pathways have evolved along with the development of the central nervous system. 

On the other hand, we aimed to understand molecular processes underlying neurological disorders and established their genetic models ranging from Drosophila to human patient-derived neurons. Importantly, we expanded our original research on the ATAXIN-2 protein complex for circadian translation to ATAXIN-2 relevant neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig’s disease). It led to our discovery of the novel molecular machinery that protects ALS patients’ neurons from degeneration. In particular, we demonstrated that ALS-causing proteins induce ribosomal stalling during their translation and a dedicated pathway called ribosome-associated quality control (RQC) co-translationally triages the neurodegenerative translation intermediates.

While RQC-dependent co-translational surveillance senses ribosomal collision on a specific mRNA as an aberrant translation event, ribotoxic stressors can induce ribosomal collisions more globally, activating translation stress pathways. Based on these observations, we reason that co-translational event may play more important roles in quality gene expression and cellular physiology. 

Our studies are thus moving forward to understand 1) how the fundamental decoding process of genetic information coordinates co-translational quality control and cellular stress signaling at molecular levels; and 2) how co-translational dynamics contributes to neuronal physiology and aging-relevant processes. We will employ molecular, genetic/genomics, biochemical, and functional imaging strategies in patient-derived iPSC/iPSC-differentiated neurons; human fibroblast; mouse primary neurons; mammalian cell cultures to address our questions and further discover co-translational mechanisms important for proteostasis, cellular stress responses, and human diseases.