PRESENILIN 1 IS A COMPONENT OF THE ADHERENS JUNCTIONS

Presenilin1(PS1)是一种完整的膜蛋白，参与家族性阿尔茨海默病(FAD)的发生发展。PS1在细胞内被加工成N-末端和C-末端片段。经典的钙粘附素是I型跨膜糖蛋白，控制细胞-细胞黏附和识别的关键事件。基于钙粘附素的细胞黏附是由连接素介导的，连接素是一种连接表面钙粘附素和皮质细胞骨架的胞质蛋白。我们使用共聚焦显微镜显示，在细胞培养中，PS1聚集在细胞与细胞的接触部位。在这些部位，PS1与以钙粘附素为基础的粘连连接的组件共定位，并与皮质细胞骨架相连。这两个PS1片段都与基于钙粘附素的黏附系统的组件形成复合体，包括E-钙粘蛋白、β-连环蛋白、伽马-连环蛋白和α-连环蛋白。此外，PS1片段存在于E-钙粘附素和β-连环素的单一复合体中。PS1与细胞表面的E-钙粘附素形成复合体，在上皮组织中，它集中在细胞-细胞接触部位。综上所述，这些数据表明PS1整合到钙粘附素/连环蛋白黏附系统中，在那里它可能在细胞间的黏附和识别中发挥作用。在大脑中，PS1片段与钙粘附素形成复合体，钙粘附素是突触的已知成分。因此，PS1突变可能通过破坏基于钙粘附素的细胞-细胞相互作用而在FAD中起作用。基于这些发现，我们建议定义PS1与基于钙粘附素的黏附系统的其他组件之间的结合，并探索PS1 FAD突变体如何影响这些结合。我们还将研究PS1是否在基于钙粘附素的细胞-细胞黏附中发挥作用，并确定FAD突变对PS1功能的影响。最后，我们将研究PS1是否是突触处钙粘蛋白/连环蛋白装置的一部分。

Presenilin1 (PS1) is an integral membrane protein involved in the development of familial Alzheimer disease (FAD). PS1 is processed intracellularly into N and C-terminal fragments. Classic cadherins are type I transmembrane glycoproteins that control critical events in cell-cell adhesion and recognition. Cadherin-based cell adhesion is mediated by catenins, which are cytosolic proteins that link surface cadherin to the cortical cytoskeleton. We used confocal microscopy to show that in cell cultures PS1 accumulates at cell-cell contact sites. At these sites, PS1 colocalizes with components of the cadherin-based adherens junctions and is linked to the cortical cytoskeleton. Both PS1 fragments form complexes with components of the cadherin-based adhesion system including E-cadherin, beta- catenin, gamma-catenin, and alpha-catenin. Furthermore, PS1 fragments are found in a single complex with E-cadherin and beta- catenin. PS1 forms complexes with cell surface E-cadherin, and in epithelial tissue it concentrates at cell-cell contact sites. Together, these data show that PS1 incorporates into the cadherin/catenin adhesion system where it probably functions in cell-cell adhesion and recognition. In the brain, PS1 fragments form complexes with cadherins which are known components of the synapse. Thus, PS1 mutations may act in FAD through disruption of cadherin-based cell-cell interactions. Based on these findings, we propose to define the bindings between PS1 and other components of the cadherin-based adhesion system and to explore how PS1 FAD mutants affect these bindings. We will also examine whether PS1 functions in cadherin-based cell-cell adhesion, and define the effects of FAD mutations on PS1 function. Finally, we will examine whether PS1 is part of the cadherin/catenin apparatus at the synapse.