Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, currently incurable. Studies in the PD field show that the gene called leucine-rich repeat kinase 2, or LRRK2 for short, is in important factor contributing to the disease. LRRK2 functions in health and disease are not defined; however, it is currently clear that the study of this gene can lead to the development of new therapies and diagnostics for PD. LRRK2 is dynamically modified in cells by small additions to specific sites of its sequence called phosphorylations. The levels of these phosphorylations on LRRK2 in cells are changed both in disease as well as after treatment with small molecules that may one day become new medications for PD. We believe that if we can understand how these changes in LRRK2 phosphorylation occur, we’ll be able to understand exactly how LRRK2 causes PD and be able to design better medications to stop the ‘diseased’ LRRK2.
This project’s overall objective are therefore to understand the role of LRRK2 phosphorylation in PD by pursuing 3 specific aims: 1) elucidate the regulation of LRRK2 phosphorylation by phosphatases, 2) determine how LRRK2 phosphorylation impacts biological functions related to PD in experimental systems, cellular and in vivo, and 3) verify the findings we make in experimental models in biosamples of PD patients.
The final conclusions of this project are:
- LRRK2 is regulated by phosphatases of the PP1 and PP2A class. This regulation is highly dynamic and organized per cluster of phosphosites;
- LRRK2 phosphorylation regulation impacts LRRK2 effects within cells, notably through governing LRRK2’s subcellular localization;
- The measure of LRRK2 phosphorylation in human biofluids shows that it is a potential biomarker for Parkinson’s disease;
- This project demonstrates that the understanding of the specific molecular event of LRRK2 phosphorylation opens perspectives in developing new PD therapies and biomarkers based on LRRK2 phosphorylation.
