The G2019S mutation in the LRRK2 gene is responsible for thousands Parkinson disease (PD) cases. But, not all of the mutation carriers will develop PD. Currently, clinicians cannot predict or discriminate on a biochemical or genetic level G2019S-LRRK2 carriers that will develop PD from those that will not. Our previous study found a convenient way to detect mutant-associated LRRK2 activity in small vesicles (exosomes) isolated from urine, and discovered the potential of this as a non-invasive biomarker to help with disease prediction. Further validation of the result is required to help individuals with this mutation, as well as understanding more about LRRK2 in PD.
We hypothesize that the higher LRRK2 activity will predict the higher risk for developing PD in LRRK2 mutation carriers, and worse disease phenotypes will correlate with LRRK2 activity levels that we predict are stable over time. The alternate hypothesis will also be tested, that LRRK2 activity changes over time, potentially responsive to disease status and severity.
In this study, exosomes will be purified from bioarchived urine samples of LRRK2 mutation carriers and controls, with and without PD. Integrating with multiple clinical assessments of motor and non-motor symptoms in PD, as well as statistical modeling, we can determine how LRRK2 activity is correlated and contributed to PD in people with or without LRRK2 mutations.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This project, besides developing a biomarker that might be useful for predicting disease risk and progression in mutation carriers, will also help to understand the underlying role of LRRK2 in PD.
Next Steps for Development:
Understanding characteristics of urinary LRRK2 as a PD biomarker. Ultimately, we hope the study will contribute to the development of a panel of biomarkers useful for determining which younger LRRK2 carriers will go on to develop PD and which will not. This may be helpful for who might consider LRRK2-targeting therapeutics when they become available in the future.