Calsenilin Interactions with PS2

描述（由申请人提供）：早老素蛋白的突变导致大多数家族性阿尔茨海默病（FAD）。在1998年，我们确定并启动了calsenilin的表征，calsenilin是一种与早老素1和早老素2的C-末端结构域相互作用的神经元钙结合蛋白。由于钙生素与两种早老素相互作用，阐明其正常的生物学作用应该提供有关这两种蛋白质共享的途径的信息，例如参与AD相关的ABeta增加的途径。自从我们最初的鉴定以来，其他研究人员已经发现，calsenilin也可以与A型K+通道相互作用并调节其活性，并作为包括强啡肽在内的许多基因的转录抑制因子。 在这一竞争性更新中，我们将继续关注钙生素及其与早老素相互作用的调节。此外，我们解决了新发现的功能calsenilin（作为A型K+通道活性和转录抑制的调节剂）的长期目的是了解任何潜在的相关性与AD相关的神经退行性变。为了实现这一点，我们提出了一系列的目标，旨在了解更多关于钙生素与其结合伙伴的相互作用的调节，并确定与蛋白质的独特的N-末端结构域相互作用的蛋白质。我们还建议评估的过程中负责的钙调蛋白从细胞质的易位的调节，在那里它大概是相互作用的早老素和K+通道，到细胞核，在那里它似乎结合到DNA，并有一个钙调节的转录抑制因子的作用。最后，我们将利用最近产生的calsenilin基因敲除小鼠，以解决的作用，calsenilin发挥早老素和K+通道贩运和功能。 本申请中描述的实验应提供关于钙生素的基本细胞生物学及其与早老素、Kv通道和控制强啡肽和c-fos表达的DNA调节元件的相互作用的基本但关键的信息。这些研究将是一个有价值的资产，不仅了解生物学的calsenilin，但也其相互作用，并最终这些信息应该是有用的，在了解早老素和K+通道相关的Ca 2+信号通路在大脑中。

DESCRIPTION (provided by applicant): Mutations in the presenilin proteins cause the majority of familial Alzheimer's disease (FAD). In 1998 we identified and initiated the characterization of calsenilin, a neuronal calcium binding protein that interacts with the C-terminal domain of presenilin 1 and presenilin 2. Because calsenilin interacts with both of the presenilins, the elucidation of its normal biological role should provide information about pathways shared by the two proteins, such as those involved in the AD-associated increases in ABeta. Since our original identification, other investigators have found that calsenilin can also interact with and modulate the activity of A-type K+ channels and act as a transcriptional repressor for a number of genes, including dynorphin. In this competing renewal we will continue to focus on calsenilin and on the regulation of its interaction with the presenilins. In addition, we address the newly identified functions of calsenilin (as a modulator of A-type K+ channel activity and transcriptional repression) with the long-term purpose of understanding any potential relevance to the neurodegeneration associated with AD. To accomplish this we propose a series of aims designed to learn more about the regulation of the interaction of calsenilin with its binding partners and to identify proteins that interact with the unique N-terminal domain of the protein. We also propose to assess the processes responsible for the regulation of the translocation of calsenilin from the cytoplasm, where it is presumably interacting with the presenilins and the K+ channel, to the nucleus, where it appears to bind to DNA and have a role as a calcium-regulated transcriptional repressor. Finally, we will utilize a recently generated calsenilin knockout mouse to address the role that calsenilin plays in presenilin and K+ channel trafficking and function. The experiments described in this application should supply fundamental but critical information about the basic cell biology of calsenilin and its interaction with the presenilins, the Kv channel and DNA regulatory element that control expression of dynorphin and c-fos. These studies will be a valuable asset for understanding not only the biology of calsenilin, but also of its interactors, and ultimately this information should be useful in understanding presenilin and K+ channel associated Ca2+-signaling pathways in the brain.