Study Rationale: We established a biorepository of blood cells from G2019S LRRK2-PD patients recruited at the Hospital Clínic de Barcelona (Barcelona). Using this cohort, we performed a phospho-proteomic pilot study by mass spectrometry and identified a differential combination of phosphorylated proteins associated with the G2019S mutation. Here we aim at validating and expanding these findings using additional G2019S and R1441G cohorts.
Hypothesis: Elucidating the molecular signaling cascade of mutant LRRK2 in LRRK2-PD patients is key to monitor PD progression, to surveil the efficiency of LRRK2 inhibitors in clinical trials, and to assess disease risk in asymptomatic LRRK2 mutation carriers.
Study Design: By state-of-the-art phospho-proteomics (collaboration with Navarrabiomed, Pamplona) we aim at validating and expanding our preliminary findings in additional G2019S and R1441G LRRK2 cohorts of similar design, size, and blood cell collection method collected at our center and at collaborating centers in Spain (Hospital Marqués-de-Valdecilla in Santander, Hospital de Donostia in San Sebastián). We expect to identify differential protein phosphorylation changes in LRRK2-PD patients affected by the G2019S and R1441G mutations that could be useful as LRRK2 pharmacodynamic biomarkers. In asymptomatic LRRK2 mutation carriers we will explore the presence of protein phosphorylation changes and evaluate their applicability as early disease biomarkers.
Impact on Diagnosis/Treatment of Parkinson’s disease: Results from this project will help: (1) to identify specific Phospho-protein changes related to mutant G2019S and R1441G LRRK2 which can be associated with disease status and disease progression into specific clinical outcomes in LRRK2-PD patients, and eventually with increased disease risk in asymptomatic LRRK2 mutation carriers; (2) to better classify not only LRRK2-PD patients into clinical subtypes but also non-genetic PD patients where the LRRK2 kinase activity could also be deregulated; and (3) to monitor the effects of LRRK2 inhibitors using peripheral blood from LRRK2-PD patients.
Next Steps for Development: Our findings hold potential for elucidating specific phosphorylation events related to LRRK2 mutations in LRRK2-PD patients and in asymptomatic LRRK2 mutation carriers, for correlating phosphorylation levels in specific proteins with clinical outcomes, and for providing PD progression and early PD biomarkers in accessible biospecimens.