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Regulation of intramembrane proteolysis by specific association of gamma-secretases and their substrates to tetraspanin enriched subdomains of the cell membrane.

γ-Secretases complexes have been intensively studied in the context of Alzheimer disease (AD) because mutations in their subunits cause genetic AD. The study of these enzymes is challenging as they are operating in the hydrophobic environment of the cell membrane which is extremely important for their activity but also poses a lot of technical problems. We think that regulation of this novel class of proteases could occur via compartmentalization of the enzyme and its substrates in specific assemblies in specialized subdomains of the plasma membrane. Some of these subdomains are organized by a very intriguing family of proteins called Tetraspanins (Tspans). Our laboratory has found that particular Tspans interact with γ- secretase and their levels are changed in AD brains. We want now to investigate how Tspans regulate the activity of γ-secretases, and even more importantly, whether they are involved in the regulation of the cleavage of their substrates. If we can find specific Tspans that activate the enzyme towards APP cleavage and Aβ generation, but not to other substrates like Notch, we might find ways to circumvent the side effects of γ-secretase inhibitors to treat AD. This scenario seems feasible based on a recent publication from the laboratory (Thathiah et al, Nat. Med. 2013) explained in further detail in the main project. Finally we also will explore the possibility to use Tspans as biomarkers for the disease.

Date:1 Oct 2013 →  31 Dec 2015
Keywords:Tetraspanin enriched subdomains
Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences