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

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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.