Function of a Novel Presenilin Binding Protein, MOCA

描述（由申请人提供）：莫卡是一个新的“衔接”蛋白家族的成员，并与早老素结合，早老素是一种导致约70%早发性家族性AD病例的蛋白质。先前的数据表明，与年龄匹配的对照相比，莫卡在AD脑的可溶性部分中丢失，与神经元缠结相关，并减少淀粉样前体蛋白（APP）的分泌和Abeta肽的产生。这些数据表明，莫卡可能在AD和其他脑功能中发挥重要作用。拟议的项目将进一步研究蛋白质的功能和潜在的机制。首先，将研究莫卡在调节细胞-细胞粘附中的作用，细胞-细胞粘附是与记忆功能有关的重要过程。将检查莫卡对细胞-细胞粘附组分（包括N-钙粘蛋白和β-连环蛋白）的表达、运输、定位和磷酸化的影响。其次，莫卡对APP分泌的作用机制将通过检验蛋白酶体参与其调节的假设来研究。第三，将使用体内动物模型通过产生莫卡空突变小鼠和果蝇来研究莫卡的生物学功能。这些动物的表型将与遗传变化的生理意义一起沿着仔细检查。上述研究将为正常大脑中莫卡功能的基本框架勾勒出轮廓，并可能导致发现理解AD的新方向。

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.