Calsenilin Interactions with PS2

描述(由申请人提供)：早老素蛋白的突变导致了大多数家族性阿尔茨海默病(FAD)。1998年，我们发现并鉴定了钙结合蛋白，这是一种与早老素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。由于钙结合蛋白与这两种早老素相互作用，对其正常生物学作用的阐明应能提供有关这两种蛋白所共有的途径的信息，例如参与AD相关的ABeta增加的途径。自从我们最初的发现以来，其他研究人员已经发现钙化蛋白还可以与A-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。 在这个相互竞争的更新中，我们将继续关注钙化蛋白及其与早老素相互作用的调节。此外，我们还讨论了新发现的钙化蛋白的功能(作为A-型K通道活性和转录抑制的调节器)，以长期了解与AD相关的神经退行性变的任何潜在相关性。为了实现这一点，我们提出了一系列目标，旨在了解更多关于钙化蛋白与其结合伙伴相互作用的调节，并识别与蛋白质独特的N-末端结构域相互作用的蛋白质。我们还建议评估负责调节钙化蛋白从细胞质到细胞核的转位的过程，在那里它可能与早老素和K通道相互作用，在那里它似乎与DNA结合并具有钙调节转录抑制物的作用。最后，我们将利用最近产生的钙化蛋白基因敲除小鼠来研究钙化蛋白在早老素和钾通道运输和功能中所起的作用。 本申请中描述的实验应提供有关钙化蛋白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调控元件相互作用的基本但关键的信息。这些研究不仅对了解钙调素的生物学特性，而且对了解其相互作用都是有价值的，最终这些信息将有助于理解脑中与早老素和K通道相关的钙信号通路。

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.