Regulation of APP Degradation and ABeta Secretion

描述(申请人提供)：我们实验室最近发现了一种新的240,000 mW的蛋白质，它与淀粉样前体蛋白(APP)的新陈代谢和AB的产生密切相关。这种蛋白被称为细胞黏附修饰物(MOCA)，在中枢神经系统神经元中表达，但不表达神经胶质细胞，与早老素和其他一些蛋白质结合，并与AD脑中的神经原纤维缠绕有关。MOCA在神经元中的表达导致APP降解速率的急剧增加和AB产生的降低。因此，这可能是一种维持神经元低水平抗体产生、延缓AD发病的体内机制。这项建议的目的是了解MOCA如何指导APP的破坏和随后AB分泌的损失。为此，将检验三个假设。第一，MOCA改变了经典的泛素-蛋白酶体途径的动力学或特异性。泛素独立的降解途径也被考虑。第二，由于最近研究表明相扑改变APP的稳定性，我们将研究相扑在MOCA依赖APP崩溃中的作用。最后，用MOCA缺失小鼠研究了MOCA蛋白的体内功能。据预测，MOCA缺陷小鼠将出现AB水平升高和发育异常，这是由于神经元中APP表达增强所致。这些研究应该清楚地定义MOCA在APP背景下的生物学作用，并导致更深入地了解APP和抗体水平是如何调节的。如果能找到专门模拟MOCA功能的小分子，它们可能被用来降低大脑中病理性AB的水平。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.