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Regulation and consequences of LRRK2 phosphorylation, a path to Parkinson’s disease therapy and diagnostics

Periodic Reporting for period 1 - RECOLOR (Regulation and consequences of LRRK2 phosphorylation,a path to Parkinson’s disease therapy and diagnostics)

Reporting period: 2015-06-01 to 2017-05-31

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.
Related to objectives 1 and 2, we started from preliminary results testing hundreds of proteins that are known to be responsible for removing phosphorylations, called phosphatases, to try to figure out which ones are working on LRRK2. We used cutting-edge molecular cell biology techniques to inhibit or activate these several of the most potent phosphatases from our initial testing and performed confirmation testing to see how that changes LRRK2 phosphorylation. These experiments are showing that there are approcimately 3-6 key phosphatases for LRRK2. This information opens the path to new studies to develop new diagnostics and new medications for PD.
Related to objective 3, we have confirmed that LRRK2 and its phosphorylation can be detected in human biosamples such as urine. These findings are paving the way to determining whether LRRK2 phosphorylation is modified in biofluids of PD patients relative to healthy subjects and have the potential of one day being used as a diagnostic test for early stages of PD.
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 at the center of the effort to detect PD in patients prior to the appearance of life-affecting symptoms and to develop therapies that will halt the progression of disease. In this regard, research efforts on using LRRK2 as a PD biomarker and on targeting LRRK2 as a therapeutic strategy are in the late phases of preclinical testing, likely to reach clinical phase testing in the near future.
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