Mob4 activity and dysfunction in Alzheimer's Disease

阿尔茨海默病中 Mob4 的活性和功能障碍

• 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
• 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' s Disease; Alzheimer' 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

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.

项目摘要 阿尔茨海默病是多基因的，然而许多人的分子功能和对疾病进展的贡献 遗传因素目前还不清楚。Mob4是一种其表达显著下调的基因 阿尔茨海默氏症，其功能尚未确定。这项研究提案的目标是 了解Mob4在神经元中的分子功能。此前的研究表明，Mob4是一个核心- STRIPAK复合体的组成部分，包含激酶和磷酸酶PP2A。Mob4包含一个 保守的磷酸结合基序，在其他Mob家族蛋白中与磷酸化的激酶结合。我们的 初步研究表明，保守的磷结合基序是神经元中Mob4功能所必需的。 我们认为，Mob4通过其磷酸结合基序，将一个激酶招募到STRIPAK中 PP2A介导的去磷酸化和降低激酶活性的复合体。目标1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，阿尔茨海默病中被破坏的两个神经元过程。初步遗传互作 研究表明，tao蛋白的活性受Mob4的调节。以往的研究表明，陶氏蛋白激酶可以 使微管相关蛋白Tau在与神经原纤维缠结相关的磷酸位点磷酸化 阿尔茨海默病的形成。Aim 2将确定Mob4是否结合并调节磷酸化陶氏激酶 并确定与Mob4相互作用的新的激酶。我们的研究将提供新的见解 Mob4功能的机制，并加深我们对Mob4功能障碍的理解 阿尔茨海默氏症。