Novel Mechanisms of RanBP9 in APP Pathogenesis

描述（由申请人提供）：由于阿尔茨海默病（AD）大脑的主要特征是一种名为Abeta （AB）的有毒蛋白质的过度积累，因此了解AB产生的生物学机制对于设计有效的AD治疗方法至关重要。AB是通过分子剪刀（称为β -和γ -分泌酶）在其亲本蛋白APP中进行两次切割而产生的。我们最近发现一种名为RanBP9的新蛋白在AD研究人员以前不知道的AB生成中起重要作用。此外，我们发现它与AB生成过程中涉及的其他重要蛋白相互作用。虽然直接抑制分泌酶是一种明显的治疗策略，但最近已经清楚，β和γ分泌酶除了产生AB外还有许多其他重要功能。因此，直接阻断分泌酶可能会产生意想不到的后果和副作用。我们的数据表明，RanBP9促进APP和β -分泌酶之间的物理接触。因此，在不直接抑制分泌酶的情况下，RanBP9可能是降低AB水平的一个新的有吸引力的治疗靶点。通过使用分子、生化和细胞生物学工具，我们提出：1)从分子上解剖RanBP9形成自结合、促进AB生成和与APP加工关键蛋白相互作用的能力；2)明确界定RanBP9在初级神经元中APP亚细胞运输和运输中的作用；3)利用小鼠转基因模型表征APP发病机制与体内RanBP9水平之间的相互作用和功能关系。公共卫生相关性：由于阿尔茨海默病（AD）大脑的主要特征是一种名为AB的有毒蛋白的过度积累，因此了解AB产生的生物学机制对于设计有效的AD治疗方法至关重要。我们最近发现一种名为RanBP9的新蛋白在AD研究者之前不知道的AB生成中起重要作用，我们发现它与其他参与AB生成的重要蛋白相互作用，促进AB生成，并且与AD具有遗传相关性。本研究旨在精确理解RanBP9如何与APP加工的各种关键蛋白相互作用，并确定RanBP9如何影响APP的运输和运输，从而在神经元和动物模型中介导AB的产生，以期开发新的治疗AD的方法。

DESCRIPTION (provided by applicant): As the major defining characteristic of Alzheimer's disease (AD) brains is the excessive accumulation of a toxic protein called Abeta (AB), understanding the biological mechanisms by which AB is generated is critical for designing effective therapeutic treatments for AD. AB is generated from two cuts made by molecular scissors (named beta- and gamma-secretases) in its parent protein, APP. We recently found that a novel protein named RanBP9 previously not known to AD investigators plays an important role in AB generation. Moreover, we found that it interacts with other important proteins involved in AB generation. Although directly inhibiting the secretases is an obvious therapeutic strategy, it has become clear recently that both beta- and gamma-secretases have many other important functions in addition to generating AB. Therefore, unintended consequences and side effects may be associated with directly blocking the secretases. Our data suggest that RanBP9 promotes the physical contact between APP and beta-secretase. Thus, RanBP9 may represent a new and attractive therapeutic target to lower AB levels without directly inhibiting the secretases. By using molecular, biochemical, and cell biological tools, we propose to 1) molecularly dissect the ability of RanBP9 to form self-associations, enhance AB generation, and interact with proteins critical for APP processing, 2) clearly define the role of RanBP9 in subcellular trafficking and transport of APP in primary neurons, and 3) characterize the reciprocal and functional relationship between APP pathogenesis and RanBP9 levels in vivo using mouse transgenic models. PUBLIC HEALTH RELEVANCE: As the major defining characteristic of Alzheimer's disease (AD) brains is the excessive accumulation of a toxic protein called AB, understanding the biological mechanisms by which AB is generated is critical for designing effective therapeutic treatments for AD. We recently found that a novel protein named RanBP9 previously not known to AD investigators plays an important role in AB generation, and we have found that it interacts with other important proteins involved in AB generation, promotes AB generation, and is genetically associated with AD. This proposal is aimed at precisely understanding how RanBP9 interacts with various proteins critical for APP processing and define the manner in which RanBP9 affects the trafficking and transport of APP to mediate AB generation in neurons and in animal models, in the hopes of developing new approach to therapeutically treat AD.