The mitochondrion plays a pivotal role in the influence of insulin receptor signalling on gamma-secretase-mediated processing

蛋白质在细胞内的许多功能中起着重要作用，它们的影响在很大程度上取决于它们在细胞内的位置以及它们如何相互作用。胰岛素是一种激素，以其调节血糖水平的作用而闻名，但其在大脑功能中的作用在很大程度上被忽视了。已知胰岛素会影响许多蛋白质的定位和相互作用，并且我们已经观察到胰岛素可以增加在线粒体上发现的称为单胺氧化酶的蛋白质的活性。此外，我们发现单胺氧化酶可以与另一种称为早老素-1的蛋白质相互作用，该蛋白质存在于细胞内的相邻结构上，并且在基因和蛋白质调控中起着核心作用。我们正在进行的工作表明，用胰岛素治疗脑细胞会影响单胺氧化酶的功能。我们建议确定胰岛素的这种影响在多大程度上是基于单胺氧化酶和早老素-1之间的相互作用的破坏，并确定这种相互作用的破坏如何迫使细胞改变其控制正常细胞功能和命运所需的基因和其他蛋白质表达的方式。我们建议首先在脑细胞培养中表征这些事件，然后使用我们的发现在已知显示单胺氧化酶和早老素-1功能变化的遗传改变小鼠中使用胰岛素修饰剂进行更集中的检查。

Proteins play an important role in many of the functions within a cell and their influence depends, in large part, on where they are located within the cell and on how they interact with each other. Insulin is a hormone that is best known for its role in regulating blood glucose levels, yet its role in brain function has been largely overlooked. Insulin is known to influence the localization and interaction of many proteins, and we have observed that insulin can increase the activity of a protein called monoamine oxidase that is found on the mitochondria. Furthermore, we have found that monoamine oxidase can interact with another protein called presenilin-1 that is found on an adjacent structure within the cell and that plays a central role in gene and protein regulation. Our ongoing work indicates that treating brain cells with insulin influences monoamine oxidase function. We propose to determine to what extent this influence of insulin is based on the disruption of the interaction between monoamine oxidase and presenilin-1, and to determine how the disruption of this interaction forces the cell to change the way that it controls the expression of genes and other proteins that are required for normal cell function and fate. We propose to initially characterize these events in brain cell cultures and then to use our findings to perform a more focused examination using an insulin modifying agent in genetically altered mice that are known to display changes in monoamine oxidase and presenilin-1 function.