Function of a Novel Presenilin Binding Protein, MOCA

描述(由申请人提供)：MOCA是一个新的‘接头’蛋白家族的成员，并与早老素结合，这种蛋白导致了大约70%的早发性家族性AD病例。先前的数据表明，与年龄匹配的对照组相比，MOCA在AD脑中的可溶性部分丢失，与神经原纤维缠结有关，并减少淀粉样前体蛋白(APP)的分泌和Aβ多肽的产生。这些数据表明，MOCA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该蛋白质的功能和潜在的机制。首先，我们将研究MOCA在调节细胞间黏附中的作用，这是一个与记忆功能有关的重要过程。MOCA对包括N-钙粘附素和β-连环素在内的细胞-细胞黏附成分的表达、运输、定位和磷酸化的影响将被检测。其次，将通过检验蛋白酶体参与其调节的假说来研究MOCA对APP分泌的影响机制。第三，将利用体内动物模型，通过产生MOCA零突变小鼠和果蝇来研究MOCA的生物学功能。这些动物的表型将被仔细研究，以及遗传变化的生理意义。上述研究将勾勒出正常大脑中MOCA功能的基本框架，并可能为理解AD提供一个新的方向。

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.