Function of a Novel Presenilin Binding Protein, MOCA

新型早老素结合蛋白 MOCA 的功能

• 批准号: 6780425
• 负责人: QI CHEN
• 金额: $ 4.89万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780425
• 关键词: Drosophilidae; amyloid proteins; binding proteins; cadherins; cell adhesion; gene targeting; genetically modified animals; laboratory mouse; neuropathology; phenotype; phosphorylation; postdoctoral investigator; presenilin; proteasome; protein degradation; protein localization; protein protein interaction; protein structure function; protein transport

DESCRIPTION (provided by applicant): MOCA is a member of a new family of 'adaptor' proteins and binds to presenilin, a protein responsible for about 70% of the early onset familial AD cases. Previous data have shown that MOCA is lost in the soluble fraction of AD brains vs. the age-matched controls, is associated with neurofibrillary tangles, and decreases the secretion of amyloid precursor protein (APP) and the production of Abeta peptides. These data suggest that MOCA may play a major role in AD and in other brain functions. The proposed project will further study the function of the protein and the underlying mechanisms. First, the role of MOCA in regulating cell-cell adhesion, an important process that has been implicated in memory function, will be studied. The effects of MOCA on the expression, trafficking, localization, and phosphorylation of cell-cell adhesion components including N-cadherin and beta-catenin, will be examined. Second, the mechanism of the MOCA effect on APP secretion will be studied by testing the hypothesis that the proteasome is involved in its regulation. Third, the biological function of MOCA will be studied using in vivo animal models by generating MOCA null-mutant mice and Drosophila. The phenotypes of these animals will be scrutinized along with the physiological significance of the genetic change. The above studies will outline a basic framework for MOCA function in the normal brain and may lead to the discovery of a new direction for understanding AD.

描述（由申请人提供）：MOCA是新的“衔接子”蛋白质家族的成员，并与Presenilin结合，Presenilin是一种蛋白质，约有70％的早期发作家族性AD病例。先前的数据表明，MOCA在AD大脑的可溶性比例与年龄匹配的对照中丢失，与神经原纤维缠结有关，并减少淀粉样蛋白前体蛋白（APP）的分泌和Abeta肽的产生。这些数据表明，MOCA可能在AD和其他大脑功能中起主要作用。拟议的项目将进一步研究蛋白质和潜在机制的功能。首先，将研究MOCA在调节细胞细胞粘附方面的作用，这是与记忆功能有关的重要过程。将检查MOCA对包括N-钙粘着蛋白和β-钙蛋白在内的细胞细胞粘附成分的表达，运输，定位和磷酸化的影响。其次，将通过测试蛋白酶体参与其调节的假设来研究MOCA效应对APP分泌​​的机制。第三，将使用体内动物模型来研究MOCA的生物学功能，通过产生MOCA NULL突变小鼠和果蝇。这些动物的表型将被仔细检查，并与遗传变化的生理意义一起进行审查。以上研究将概述正常大脑中MOCA功能的基本框架，并可能导致发现新的方向以理解AD。