Research

Cells rely on the efficient sensing and the integration of a constant flow of information from the intracellular and extracellular environment. Membrane proteins transmit extracellular signals by triggering intracellular signalling cascades. One example of such membrane-embedded complexes are γ-Secretases. They have been intensively studied as intramembrane proteases that control numerous cell signalling cascades regulating a wide range of physiological processes. They are also intimately connected to disease, as mutations in the γ-Secretase complex cause early onset, autosomal dominant Alzheimer’s disease and acne inversa, a chronic skin disorder. Dysregulation of γ-Secretase-mediated proteolysis has also been linked to cancer, and growing evidence supports its involvement in autoimmune and infectious diseases. γ-Secretases thus represent a unique multifaceted proteolytic system at the crossroad of numerous physio-pathological processes. Nevertheless, central questions related to their mechanisms, biological roles and contribution to disease remain unaddressed.

The limited understanding has been, and in fact still is, a major obstacle for the development of safe drugs targeting γ-Secretase. The research in our lab builds on the premise that a solid mechanistic understanding of life processes and their dysregulation in disease is critical for therapeutic development. That is why we take a genetically and structurally led bottom-up approach to answer fundamental questions about γ-Secretase biology:

• How does γ-Secretase work? 
• How does its dysregulation lead to disease? 
• How does γ-Secretase dysfunction translate to cellular toxicity, neurodegeneration and other associated clinical phenotypes (e.g. spastic paraparesis, myoclonus and aphasia)?

We hope to offer key insights into how these fascinating molecular switches control fundamental cellular processes, and to provide new tools to investigate their associated biology. In addition, our research efforts may inspire original, therapeutic strategies targeting γ-Secretase in the context of Alzheimer's disease.

Throughout our studies, our lab has accumulated extensive expertise in the development of nanobodies, single-domain antibodies that consist of a single monomeric variable antibody domain. Nanobodies represent an innovative, ground-breaking class of molecules, uniquely suited for targeting conformational protein assemblies.

We integrate state-of-the-art biochemistry, enzymology, nanobody technology and model membrane electrophysiological approaches to determine the structural strategies and the molecular mechanisms involved in substrate recognition, the stabilization of enzyme-substrate interactions, product release etc. We also use nanobodies targeting relevant protease conformations in cryo electron microscopy.