Identifying conserved cellular mechanisms involved in Alternating Hemiplegia of Childhood

About This Grant

Project Summary This revised proposal focuses on disease caused by dominant mutations in ATP1A3, a Na+/K+-ATPase pump that plays pivotal roles in maintaining excitable cell function. ATP1A3 missense patient alleles cause various ATP1A3 diseases; here we focus on Alternating Hemiplegia of Childhood (AHC). Critical questions in the AHC field include how do patient alleles alter protein function, what are the molecular and cellular consequences driving disease-associated dysfunction, and which proteins and pathways should be targeted for therapy development? The proposed studies are focused on understanding, at a molecular level, how ATP1A3 patient alleles cause disease and finding therapeutic targets. In Aim 1 of this R21 proposal, we use newly developed C. elegans AHC models and a functional genetic approach to identify conserved suppressor genes. In Aim 2, assess which cellular mechanisms are relevant to AHC pathophysiology. In Aim 3 we undertake a genetic screen to identify gene whose perturbation suppresses defects in a C. elegans AHC model. Combined these studies will 1) increase our understanding of how common AHC alleles perturb cellular function, leading to disease, and 2) swiftly identify genes and pathways that can be targeted for therapy development.