Mob4 activity and dysfunction in Alzheimer's Disease

项目摘要 阿尔茨海默氏病是多基因的，但许多基因的分子功能和对疾病进展的贡献， 遗传因素还不清楚。Mob 4是一种基因，其表达在哺乳动物中显著下调。 阿尔茨海默氏病，其功能尚未确定。这项研究计划的目标是 了解Mob 4在神经元中的分子功能。先前的研究表明，Mob 4是一个核心- STRIPAK复合物的组分，其含有激酶和磷酸酶PP 2A。Mob 4包含 保守的磷酸结合基序，其在其它Mob家族蛋白中结合磷酸化激酶。我们 初步研究表明，保守的磷酸结合基序是Mob 4在神经元中发挥功能所必需的。 我们认为Mob 4的功能是通过其磷酸结合基序将激酶募集到STRIPAK中 PP 2A介导的去磷酸化和激酶活性的降低。目标1将解决如果 Mob 4的磷酸结合基序是调节轴突运输和长期记忆所必需的 形成，这两个神经元过程在阿尔茨海默病中被破坏。初步遗传互作 研究表明Tao激酶活性受Mob 4调节。先前的研究表明，Tao激酶可以 在与神经元缠结相关的磷酸化位点磷酸化微管相关蛋白Tau 阿尔茨海默病的形成。目的2将确定Mob 4是否结合并调节磷酸-Tao激酶 活性并鉴定与Mob 4相互作用的新型激酶。我们的研究将提供新的见解， Mob 4功能的机制，并推进我们对Mob 4功能障碍如何有助于 老年痴呆症

Project Summary Alzheimer’s disease is polygenic, yet the molecular functions and contributions to disease progression of many genetic factors are not understood. Mob4 is a gene whose expression is significantly downregulated in Alzheimer’s disease and whose function is yet to be determined. The goal of this research proposal is to understand the molecular functions of Mob4 in neurons. Previous studies have shown that Mob4 is a core- component of the STRIPAK complex, which contains kinases and the phosphatase PP2A. Mob4 contains a conserved phospho-binding motif that in other Mob family proteins binds phosphorylated kinases. Our preliminary studies show that the conserved phospho-binding motif is required for Mob4 function in neurons. We propose that Mob4 functions, through its phospho-binding motif, to recruit a kinase into the STRIPAK complex for PP2A-mediated dephosphorylation and a reduction in kinase activity. Aim 1 will address if the phospho-binding motif of Mob4 is required for regulation of axonal transport and for long-term memory formation, two neuronal processes that are disrupted in Alzheimer’s disease. Preliminary genetic interaction studies suggest that Tao kinase activity is regulated by Mob4. Previous studies show that Tao kinase can phosphorylate the microtubule associated protein Tau at phospho-sites associated with neurofibrillary tangle formation in Alzheimer’s disease. Aim 2 will determine if Mob4 binds and regulates phospho-Tao kinase activity and identify novel kinases that interact with Mob4. Our studies will provide new insights into the mechanism of Mob4 functions and advance our understanding of how Mob4 dysfunction contributes to Alzheimer’s disease.