Date of Graduation
Eberly College of Arts and Sciences
Microbiology, Immunology, and Cell Biology
gamma-Secretase is an enzymatic complex critical to amyloid formation and other important pathophysiological processes. Non-specific gamma-secretase inhibitors are not ideal for intervention of familial Alzheimer's disease. The four essential include Presenilin (PS1 or PS-2), APH-1, Pen-2, nicastrin (Nct). Also gamma-secretase cleaves a variety of substrates (over 30). But different sites are cleaved even in a single substrate and no consensus sequence for cleavage by gamma-secretase is identified. We hypothesize that consensus compositional sequence (or functional domain) in components of gamma-secretase and/or its substrates should exist during gamma-secretase regulation and specific gamma-secretase inhibitor based on such consensus sequence (or functional domain) may act as a therapeutic intervention for familial Alzheimer's disease. We divide our research into two stages. At Stage I, we find the candidates by the methods of bioinformatics. The less, the better. By using the resources of genetic and protein databases and tools, selecting software to apply sequence analysis, modeling and simulation, and pattern recognition of gamma-secretase regulation, we identify candidates of consensus sequences (or functional domains). At Stage II, we use the traditional biological methods to verify the critical role of the candidates including the protein purification, recognition, and functional domain interaction. This thesis work is particularly focused on Stage I.
Nan, Fei, "Bioinformatic Study of gamma-Secretase and its Substrates" (2008). Graduate Theses, Dissertations, and Problem Reports. 4408.