Project number 24

Degradomic approaches to study intramembrane proteolysis involved in neurodegenerative diseases

Alzheimer's and Parkinson's Disease are major problems for human health. While the genetics of these disorders have been clarified to a large extent, translating this knowledge into mechanisms and drug targets is the real challenge for the next years.
We are studying the proteolytic enzymes that perform intramembrane proteolysis. These enzymes, more specifically the gamma-secretases and PARL, are key players in Alzheimer’s (AD) and Parkinson’s (PD) disease and interesting drug targets. However, they are also essential for other cellular functions and biological processes. Here we propose to characterize the degradome, i.e. all the different substrates that are cleaved by gamma secretases and PARL. Although many substrates have been postulated, little is known about the substrates that are processed in vivo in the brain. Here we propose to develop a novel proteomics technique suitable to detect protease cleavage sites in membrane proteins, based on COFRADIC and TAILS technologies. The PhD candidate will learn both methods and apply these to clarify these crucial biological and pathological questions. The proposal is a unique collaboration equally balanced between the VIB Laboratory for the Research of Neurodegenerative Diseases (a top level laboratory regarding AD and PD research (De Strooper and Karan, Cell 2016)) and the VIB Proteomics Expertise Center (a state-of-the art proteomics core facility (Staes, Nat Protocols 2011)), which have a consolidated collaboration in this field. The project will provide the candidate with a unique expertise in the field of neurodegenerative disorders and mass spectrometry-based proteomics.

Alzheimer’s disease, mass spectrometry, intramembrane proteolysis, proteomics, mitochondria

Bart De Strooper, VIB Center for the Biology of Disease, KU Leuven, Leuven
Francis Impens, VIB Medical Biotechnology Center, UGent, Gent