RECOLOR · Regulation and consequences of LRRK2 phosphorylation, a path to Parkinson’s disease therapy and diagnostics
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-06-01 → 2017-05-31
- EU contribution
- €185,076
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Regulation and consequences of LRRK2 phosphorylation,a path to Parkinson’s disease therapy and diagnostics
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.
Data: CORDIS, © European Union
Project objective
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, currently incurable. Studies in the PD field show that leucine-rich repeat kinase 2 (LRRK2) is both a major player in PD pathogenesis and a promising PD therapeutic target. LRRK2 functions in health and disease are not defined; however the applicant and others have shown that LRRK2 phosphorylation is the key to understanding LRRK2 biology. This project’s goal is 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 LRRK2 phosphorylation downstream phenotypes in cellular models through transcriptome profiling, protein translation profiling and protein tau related phenotypes, and 3) verify these findings from experimental models in PD biosamples. The project builds on the applicant’s extensive expertise in the field of LRRK2 biology (24 papers in 8 years) required for aim 1 and will leverage expertise on PD biosample analysis of the host institution (training for aims 2 and 3). The research program will be performed at the JPA research center (a mixed Inserm-Lille 2 University-Lille University Hospital center for excellence research, Lille, France), with a network of strategically chosen collaborating research groups locally and internationally, coordinated by the applicant. The study of LRRK2 phosphorylation in experimental models and translation of experimental results to clinical samples will reveal the most relevant molecular mechanisms of LRRK2 in PD which can be exploited in follow up work as diagnostic biomarkers and targeted for disease-modifying therapy. Given the importance of PD and neurodegeneration in Europe, this project is fertile ground for a high visibility fellowship and will reposition the applicant in the international neurodegenerative diseases research community by adding a clinical translation dimension to his signalling neurobiologist profile.
Original text from CORDIS.
Participants
- UNIVERSITE DE LILLE · LilleCoordinatorFrance
Links
Data: CORDIS, © European Union