Kinase Dysfunction in Autism and Neurodevelopmental Disorders

摘要 在神经元发育的每一步，从神经发生开始，激酶信号就被精心地编排起来。 到神经元与功能性突触网络的整合。通过高度特异的底物磷酸化， 蛋白激酶调节神经元的生长、活性及其可塑性。尽管有越来越多的证据表明 和激酶功能障碍在神经发育障碍(NDD)中的致病作用，其机制是 人类亲属组控制着神经元的发育，其功能障碍在疾病中的表现仍然是主要的。 神经发育生物学领域的空白。在这项提案中，我们将研究蛋白激酶的作用 TAOK1基因突变与自闭症谱系障碍、巨头症密切相关 和神经发育迟缓。根据我们的初步发现，这项研究的中心假设 有一种观点认为，TAOK1是一种多效性的激酶，它通过直接 结合磷脂和重塑神经细胞膜，而TAOK1信号通路的功能障碍导致 神经发病机制。我们的数据表明：(A)新城疫中的从头突变和遗传性TAOK1突变都会导致异常 破坏神经元形态和功能的神经细胞膜延伸和(B)TAOK1可以直接结合 肌醇磷脂富含在质膜上。通过整合创新方法 蛋白质组学、化学遗传学、结构生物学、干细胞技术和人类疾病相关模型 系统，我们试图(Aim1)了解TAOK1信号介导神经元的机制 发展，(AIM2)确定了支配TAOK1膜结合和重塑的生物学原理， 和(Aim3)建立人类干细胞衍生的TAOK1相关疾病的神经元模型，以便 确定由于TAOK1基因缺陷引起的发育紊乱和磷酸蛋白质组的变化 发信号。这些研究将提供一个全面的理解，高度自信的基因在 神经发育障碍的病因学。

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.