Study Rationale:
Several genes play a crucial role in Parkinson's disease (PD). The most common genetic cause of PD is mutations in the gene encoding LRRK2, a very large and complex protein with different enzyme (accelerates chemical reactions) functions. Targeting the multiple enzymatic functions of LRRK2 represents a very attractive approach for designing novel therapeutics for PD that requires detailed structural and mechanistic information on LRRK2. However, LRRK2 is a notoriously challenging protein to study on a molecular level.
Hypothesis:
We will develop domain- and conformation-specific nanobodies to study the structure of LRRK2 and to characterize LRRK2 on a molecular level, a necessary starting point for the search into a novel therapeutic strategy.
Study Design:
Nanobodies are small, stable protein fragments derived from a special type of antibodies (immune system cells) present in camelids such as llamas. In recent years, it has been shown that nanobodies are exquisite tools that can block dynamic proteins into a certain configuration (structure). This stabilization makes it possible to study the structure of proteins that normally rapidly change form. We plan to generate, select and characterize nanobodies that bind LRRK2 in a specific manner.
Impact on Diagnosis / Treatment of Parkinson's disease / Next Steps for Development:
Nanobodies will be used to elucidate the structure of LRRK2 via X-ray crystallography and/or cryo-electron microscopy (imaging techniques). The structural information gained in this project will be key to design drugs targeting LRRK2. These nanobodies are interesting tools for further research into LRRK2 and we can use them as probes to 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.