Regulation of APP Degradation and ABeta Secretion

描述（由申请人提供）：我们的实验室最近发现了一种新的24万MW蛋白，它与淀粉样蛋白前体蛋白（APP）的代谢和AB的产生密切相关。这种蛋白被称为细胞粘附修饰因子（MOCA），在中枢神经系统神经元中表达，但在神经胶质细胞中不表达，与早老素和许多其他蛋白质结合，并与阿尔茨海默病大脑中的神经原纤维缠结有关。神经元中MOCA的表达导致APP降解速率的急剧增加和AB产量的降低。因此，这可能是维持神经元低水平Ab产生并延缓AD发病的体内机制。本文的目标是了解MOCA如何指导APP的破坏以及随后AB分泌的丧失。为此，将测试三个假设。首先，MOCA改变了经典泛素-蛋白酶体途径的动力学或特异性。也考虑了与泛素无关的降解途径。其次，由于最近有研究表明SUMO化会改变APP的稳定性，我们将研究SUMO在MOCA依赖性APP分解中的作用。最后，建立MOCA缺失小鼠来研究MOCA蛋白在体内的功能。据预测，moca缺失小鼠会出现AB水平升高和神经元中APP表达增强导致的发育异常。这些研究应该清楚地定义MOCA在APP背景下的生物学作用，并进一步了解APP和Ab水平是如何被调节的。如果能找到专门模拟MOCA功能的小分子，它们可能被用于降低大脑中病理性AB水平。此外，了解细胞如何调节蛋白质的降解对于研究广泛的疾病，特别是那些以细胞内蛋白质积累为特征的神经系统疾病至关重要。

DESCRIPTION (provided by applicant): Our Laboratory has recently discovered a novel 240,000 MW protein that is intimately involved in the metabolism of amyloid precursor protein (APP) and AB production. The protein, called modifier of cell adhesion (MOCA), is expressed in CNS neurons but not glia, binds to presenilin and a number of other proteins, and is associated with neurofibrillary tangles in AD brain. The expression of MOCA in neurons leads to a dramatic increase in the rate of APP degradation and a lowering of AB production. It may therefore be an in vivo mechanism for maintaining a low level of Ab production by neurons and delaying the onset of AD. It is the goal of this proposal to understand how MOCA directs the destruction of APP and the subsequent loss of AB secretion. Toward this end, three hypotheses will be tested. The first is that MOCA alters either the kinetics or specificity of the classical ubiquitin-proteasome pathway. Ubiquitin independent degradation pathways are also considered. Second, because it has recently been shown that sumoylation alters the stability of APP, we will study the role of SUMO in MOCA dependent APP breakdown. Finally, MOCA null mice have been made to study the in vivo function of the MOCA protein. It is predicted that MOCA-deficient mice will have increased levels of AB and developmental abnormalities resulting from enhanced APP expression in neurons. These studies should clearly define the biological role of MOCA in the context of APP and lead to greater insight into how APP and Ab levels are regulated. If small molecules could be found which specifically mimic MOCA function, they could potentially be used to lower pathological AB levels in the brain. In addition, understanding how cells regulate the degradation of proteins is critical to the study of a wide range of diseases, particularly those in the nervous system that are characterized by the intracellular protein accumulation.