Grant: CIHR Fellowship

Transmembrane proteins are a category of proteins localized to the cell membrane that play important roles in brain communication such as stabilizing synapses and receiving extracellular signals. Mutations in the genes that make these proteins can sometimes cause them to get stuck inside the cell, leading to various brain disorders. We believe that if we can identify drugs that move these mutant proteins back to the cell membrane, it might help with the patient's symptoms. My long-term goal is to create a method to find drugs that can do this. As a first step, I am focusing on a mutation in the NLGN4X gene, which is linked to a high risk of developing severe autism spectrum disorder (ASD). This mutation causes the NLGN4X protein to get stuck inside the cell, leading to defects in brain development and communication. In this project, I will: Aim 1. Use cells from a NLGN4X patient to develop a method that rapidly and reproducibly measures how much of the mutant NLGN4X protein reaches the cell membrane. Aim 2. Use this method to find drugs that can help the protein move to the membrane. Aim 3. Test these candidate drugs in patient-derived brains organoids, which are a small, lab-grown cluster of neural cells that mimic aspects of the human brain structure and function, for improvements in brain connections. The short-term goal is to help improve ASD symptoms in individuals with NLGN4X mutations. Longer term, this project could lead to a method to rescue stuck membrane proteins in other diseases.