Study Rationale:
Parkinson's disease (PD) mutations in the LRRK2 protein have been linked to decreased GTPase (enzyme that binds to G proteins) activity and increased kinase (enzyme that modifies a protein) activity. Many LRRK2-specific brain-penetrant kinase inhibitors have been developed but many have major side effects. In addition, different PD-linked LRRK2 mutations likely have different effects on the LRRK2 protein. Therefore, alternative approaches targeting other LRRK2 sites that may modify kinase structure could significantly improve therapeutic benefits. This experiment aims to identify new therapeutics for LRRK2-linked PD and provide a proof-of-concept study.
Hypothesis:
LRRK2 is an excellent target for PD research, as it contains multiple enzyme functions within one protein. To develop new therapeutic strategies, we will investigate how different types of LRRK2 sites interact and regulate each other at the molecular and atomic level.
Study Design:
To fully explore new potential LRRK2 targets, it is essential to obtain a detailed understanding of how LRRK2 is activated. Recently, high quality full-length LRRK2 has been purified. Using a novel directed evolution approach, we showed, for the first time, how to express different types of wild type- and PD-related LRRK2 fragments. In this study, we will use these unique tools to provide in-depth characterization of the biochemical, biophysical and structural properties of LRRK2, which will be crucial for the exploration and identification of new therapeutic targets for LRRK2-linked PD.
Impact on Diagnosis/Treatment of Parkinson's disease:
It is currently unknown if kinase structure is the single output of the LRRK2 protein. Furthermore, some PD-related defects may be independent of kinase activity, suggesting that, in addition to kinase inhibition, other strategies should be considered to develop effective treatments. The results of our study will be instrumental in identifying alternative therapeutic targets for LRRK2-linked PD.
Next Steps for Development:
Our study will identify new potential therapeutics for LRRK2-linked PD. Collaboration with The Michael J. Fox Foundation's LRRK2 Consortium and industry partners will help accelerate development of the most promising compounds identified.