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240，000 MW蛋白质，其密切参与淀粉样前体蛋白（APP）的代谢和AB的产生。这种蛋白质称为细胞粘附调节剂（莫卡），在CNS神经元中表达，但在神经胶质中不表达，与早老素和许多其他蛋白质结合，并与AD脑中的神经元缠结相关。莫卡在神经元中的表达导致APP降解速率的显著增加和AB产生的降低。因此，这可能是维持神经元产生低水平抗体并延迟AD发作的体内机制。该提案的目标是了解莫卡如何指导APP的破坏和随后的AB分泌丧失。为此，将测试三个假设。首先是莫卡改变经典的泛素-蛋白酶体途径的动力学或特异性。还考虑了不依赖于泛素的降解途径。第二，因为最近已经表明SUMO化改变APP的稳定性，我们将研究SUMO在莫卡依赖性APP分解中的作用。最后，制备莫卡缺失小鼠以研究莫卡蛋白的体内功能。据预测，MOCA缺陷小鼠的AB水平会增加，并且由于神经元中APP表达增强而导致发育异常。这些研究应该清楚地定义莫卡在APP背景下的生物学作用，并导致更深入地了解APP和Ab水平是如何调节的。如果能够找到特异性模拟莫卡功能的小分子，它们可能会用于降低大脑中的病理性AB水平。此外，了解细胞如何调节蛋白质的降解对于研究各种疾病至关重要，特别是那些以细胞内蛋白质积累为特征的神经系统疾病。

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.