Mob4 activity and dysfunction in Alzheimer's Disease

阿尔茨海默病中 Mob4 的活性和功能障碍

基本信息

批准号：
10667178
负责人：
Amanda Louise Neisch
金额：
$ 23.25万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667178
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease patient Axonal Transport Behavioral Binding Binding Proteins Biochemistry Biological Assay Biological Models Cell physiology Complex Data Defect Dementia Development Disease Disease Progression Drosophila genus Endosomes Functional disorder Genes Genetic Goals Hippocampus Image Impairment Late Onset Alzheimer Disease Link Mediating Memory Microtubule-Associated Proteins Mitochondria Molecular Motor Multiprotein Complexes Nervous System Neurodegenerative Disorders Neurons Neuropeptides Organelles Pathogenesis Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphoserine Phosphotransferases Process Protein Dephosphorylation Protein Family Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Regulation Research Research Proposals Role Scaffolding Protein Testing Therapeutic Threonine insight long term memory neurofibrillary tangle formation novel novel therapeutic intervention prevent protein function protein transport public health relevance recruit scaffold treatment strategy

项目摘要

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.

项目概要阿尔茨海默病是多基因的，但许多疾病的分子功能和对疾病进展的贡献 Mob4 是一个在人体内表达显着下调的基因。阿尔茨海默病及其功能尚未确定。这项研究计划的目标是。之前的研究表明 Mob4 是一个核心 STRIPAK 复合物的组成部分，包含激酶和磷酸酶 PP2A。其他 Mob 家族蛋白中的保守磷酸结合基序与磷酸化激酶结合。初步研究表明，保守的磷酸结合基序是 Mob4 在神经元中发挥功能所必需的。我们认为 Mob4 通过其磷酸结合基序发挥作用，将激酶招募到 STRIPAK 中 PP2A 介导的去磷酸化和激酶活性降低的复合物将解决如果 Mob4 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，在阿尔茨海默氏病中被破坏的两个神经元过程。研究表明，Tao 激酶活性受 Mob4 调节。之前的研究表明，Tao 激酶可以。在与神经原纤维缠结相关的磷酸位点磷酸化微管相关蛋白 Tau Aim 2 的形成将决定 Mob4 是否结合并调节磷酸-Tao 激酶。我们的研究将为 Mob4 提供新的见解。 Mob4 功能机制并加深我们对 Mob4 功能障碍如何导致的理解阿尔茨海默病。