Kinase Dysfunction in Autism and Neurodevelopmental Disorders

摘要

ABSTRACT Kinase signaling exquisitely orchestrates each step of neuronal development, beginning at neurogenesis to neuronal integration into functional synaptic networks. Through their highly specific substrate phosphorylation, protein kinases regulate neuronal growth, activity and their plasticity. Despite the increasing evidence for a critical and causative role of kinase dysfunction in neurodevelopmental disorders (NDD), the mechanisms through which the human kinome controls neuronal development and how its dysfunction manifests in disease remain major gaps in the field of neurodevelopmental biology. In this proposal, we will investigate the role of protein kinase TAOK1, genetic mutations in which have been strongly associated with autism spectrum disorder, macrocephaly and neurodevelopmental delay. Based on our preliminary findings, the central hypothesis of this research proposal is that TAOK1 is a pleiotropic kinase that regulates neuronal development through its ability to directly bind phospholipids and remodel the neuronal membrane, and that dysfunction in TAOK1 signaling lead to neuropathogenesis. Our data show that (a) both de novo and inherited TAOK1 mutations in NDD induce aberrant neuronal membrane extensions that disrupt neuronal morphology and function and (b) TAOK1 can directly bind phosphoinositides enriched in the plasma membrane. Through integration of innovative approaches in proteomics, chemical-genetics, structural biology, stem cell technology and human disease relevant model systems, we seek to (Aim1) understand the mechanisms through which TAOK1 signaling mediates neuronal development, (Aim2) determine the biological principles that govern TAOK1 membrane binding and remodeling, and (Aim3) generate human stem cell derived neuronal models of TAOK1 associated disease in order to determine developmental perturbations as well as phosphoproteomic changes due to deficits in TAOK1 signaling. These studies will provide a comprehensive understanding of the role of a high confidence gene in the etiology of neurodevelopmental disorders.