Novel Mechanisms of RanBP9 in APP Pathogenesis

描述（由申请人提供）：由于阿尔茨海默病（AD）大脑的主要定义特征是称为Abeta（AB）的毒性蛋白质的过度积累，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是由分子剪刀（命名为β-和γ-分泌酶）在其亲本蛋白APP上进行两次切割产生的。我们最近发现，一种以前不为AD研究人员所知的新蛋白RanBP 9在AB产生中起着重要作用。此外，我们发现它与其他参与AB生成的重要蛋白质相互作用。虽然直接抑制分泌酶是一种明显的治疗策略，但最近已经清楚的是，β-和γ-分泌酶除了产生AB外还具有许多其他重要功能。因此，意想不到的后果和副作用可能与直接阻断分泌酶有关。我们的数据表明RanBP 9促进APP和β-分泌酶之间的物理接触。因此，RanBP 9可能代表一种新的和有吸引力的治疗靶点，以降低AB水平而不直接抑制分泌酶。通过使用分子、生物化学和细胞生物学工具，我们提出：1）从分子上剖析RanBP 9形成自缔合、增强AB生成以及与APP加工关键蛋白相互作用的能力，2）明确定义RanBP 9在原代神经元中APP的亚细胞运输和转运中的作用，和3）使用小鼠转基因模型表征体内APP发病机制和RanBP 9水平之间的相互关系和功能关系。公共卫生相关性：由于阿尔茨海默病（AD）大脑的主要定义特征是一种称为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。我们最近发现一种以前不为AD研究者所知的名为RanBP 9的新蛋白在AB生成中起着重要作用，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，并与AD遗传相关。该提案旨在精确理解RanBP 9如何与APP加工的各种关键蛋白相互作用，并定义RanBP 9影响APP的运输和转运以介导神经元和动物模型中AB产生的方式，以期开发治疗AD的新方法。

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.