Analysis of the function of Presenilin in Development and Neurodegeneration in Drosophila melanogaster
Final Report Abstract
Proteins are not only required as a foundation for the structural features characterizing different cell types and the ultimate physical appearance of a multi-cellular organism but also play important roles in the decision making processes, which are underlying the development of a higher organism from the fertilized egg (single cell) to the multi-cellular adult (billions of cells). A very important aspect in this regard, are communication procedures between cells, which allow for the coordination of processes in larger populations of cells. For instance, a signal is emitted from one cell, received from the neighboring cell and translated into an action. This event is called signal transduction and requires the activity of a defined group of proteins. One can compare signal transduction with a chain of commands within a company, which leads to a certain action (e.g. production of a certain product). In this scenario, proteins not only represent the involved personal but the hardware as well: The CEO, located in the head quarter (signal sending cell), sends an E-Mail message (signal) to the plant (signal receiving cell) where it is received by the foreman (receptor), who translates it into certain actions (signal transduction). All the proteins required for this chain of command form the so-called signaling pathway. Several types of these pathways exist and are used repeatedly during the development of organisms as different as the fruit fly Drosophila and humans. Intriguingly, many of the most important signaling pathways have been discovered and analyzed in Drosophila, and only owing to these analyses their importance for the development of humans was detected subsequently. Thus, Drosophila is a wonderful tool to study the precise function of these pathways despite the obvious differences in physical appearance and structure between humans and Drosophila. In the meantime, it has become clear that components of the signaling pathways not only are necessary for the development of an organism but play similarly important roles for the development of diseases. For instance, the activity of the protein Presenilin is required for several pathways. It functions like a scissor and precisely cleaves other proteins, which is important for the normal development of a fruit fly as well as for the development of a human being. However, malfunction of the protein itself, and of the pathways depending on it, contributes to diseases like Alzheimer’s disease and breast cancer in humans. It is therefore not surprising that Presenilin, and its associated pathways, are in the focus of many studies in the field of medical research. Nevertheless, many obscurities exist and, for example, it is still unclear how the scissor precisely functions and how proteins are selected to be cleaved. To address these questions, we decided to use the Drosophila model. The results we obtained in the past years provided valuable insights and suggest that the decision, whether a protein is cleaved by Presenilin or not, depends on additional factors. We have identified a variety of proteins, which are in direct contact with Presenilin and may influence its cleavage efficiency. Furthermore, we isolated a multitude of proteins that are involved in one of the Presenilin-dependent pathways (Notch signaling pathway), and might play important roles for the development and progression of cancer in humans. Currently, we are in the process to make these results available to the scientific community, to boost research in this area and given the fact that the analysis of all our results is beyond the compass of our research power. In future studies, we will sort the identified proteins to certain positions within the chain of commands of the Notch signaling pathway, and identify those proteins required for Presenilin activity. In collaboration with clinicians, we will also try to evaluate if our results can be used to make prognosis for the development of tumors in individual patients and if this information can then be used to develop a more accurate treatment. However, these are long-term goals and will require sustained research efforts.
Publications
- 2007. Rhomboid cleaves Star to regulate the levels of secreted Spitz. EMBO J 26(5): 1211-1220
Tsruya R., Wojtalla A., Carmon S., Yogev S., Reich A., Bibi E., Merdes G., Schejter E., and Shilo BZ.
- 2009. About combs, notches, and tumors: Epigenetics meets signaling. Dev Cell. Oct;17(4):440-2
Merdes G., and Paro R.
