Grant: CIHR Fellowship

Cells contain several nano-machines composed of protein molecules that carry most of the molecular functions required to keep a cell alive. For these nano-machines to function properly, their component protein molecules need to be synthesized and delivered to the right place at the right time. Human cells contain a billion different protein molecules and ensuring their correct localization creates a large logistical challenge for our cells. First, cells need to ensure that newly made proteins get to the right part of the cell and assemble into functional machines. Second, cells have to recognize errors in protein maturation and target the defective products for degradation. Both processes are essential to all living cells, and even subtle problems in protein maturation or quality control has been shown to lead to many known genetic and neurological disorders such as epilepsy. 50% of all idiopathic-generalized epilepsy is caused by genetic mutations in molecular machines called the GABA A receptors that are one of the major receptors for signal transmission in our nervous system. Fundamental studies in the field of cell biology have shown that multiple pathways exist in cells to target simple model proteins to their correct sub-cellular location. However, we still do not understand the specific pathway used by complex proteins such as the GABA A receptors that can be formed by 19 different proteins in our body. In this study, we propose assays and experiments by which we can identify the factors involved in assembly of GABA A receptors. Many of the assays proposed in this study were developed in our lab and have been made possible due to recent breakthroughs in gene editing and single-molecule technologies. With these tools, we aim to build a detailed map of cellular pathways involved in maturation of GABA A receptors present in our body. This can guide health researchers and clinicians to better understand the pathological basis of epilepsy-causing mutations.