Novel Mechanisms of RanBP9 in APP Pathogenesis

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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.