Wim Versées, staff scientists at the VIB-VUB Center for Structural Biology, received a Michael J. Fox Foundation grant. The foundation provides funding for translational and clinical research supporting Parkinson’s-related breakthroughs.
Wim Versées (VIB-VUB): “I am very excited to receive this grant as it will allow us to develop Nanobodies as innovative tools to study the role of a protein called LRRK2 in Parkinson’s disease. Hopefully, this will pave the way for developing new therapeutic strategies in the longer run”.
Development of Nanobodies as novel tools to characterize LRRK2, a potential drug target for Parkinson’s Disease
Several genes are known to play a crucial role in Parkinson’s disease (PD). The most common genetic cause of PD are mutations in the gene encoding LRRK2, which is a very large and complex protein with different enzymatic functions. Targeting these multiple enzymatic functions of LRRK2 thus forms a very attractive approach to design novel therapeutics for PD. Therefore, detailed structural and mechanistic information on LRRK2 is required. However, so far this protein has been notoriously challenging to study on a molecular level.
We will develop domain and conformation-specific Nanobodies to elucidate the 3-dimensional structure of LRRK2 and to characterize LRRK2 on a molecular level. This is a necessary starting point for the search of novel therapeutic strategies. Nanobodies are small, stable protein fragments derived from a special type of antibodies present in camelids such as llamas. In recent years it has been shown that Nanobodies are exquisite tools to block dynamic proteins into a certain configuration. This stabilization makes it possible to study the structure of proteins that normally rapidly change conformation.
Supported by the Michael J. Fox Foundation grant, we will now generate, select and characterize Nanobodies that bind LRRK2 in a conformation-specific manner. These Nanobodies will subsequently be used to elucidate the structure of LRRK2 via X-ray crystallography and/or cryo-electron microscopy. The structural information that we will gain in this project will be key to design drugs targeting LRRK2. Finally, these Nanobodies can also be interesting tools for further research of LRRK2. Using them as probes we can monitor the function and localization of LRRK2 in cells. This will yield crucial information regarding the role of LRRK2 in neurons in health and disease.
The project is a collaboration with Jan Steyaert (VIB-VUB), Johannes Gloeckner (DZNE) and Arjan Kortholt (University of Groningen).