Study Rationale: Mutations associated with Parkinson’s disease (PD) elevate the activity of a protein called Leucine-rich repeat kinase 2 (LRRK2). Kinases add phosphate groups to other proteins and to themselves. Activated LRRK2 often tags itself with a phosphate group at residue S1292, and autophosphorylated LRRK2 is emerging as a potential biomarker for PD. However, current detection methods are limited. In this study, we will leverage antibodies against LRRK2 with a light-emitting enzyme called luciferase to develop a rapid, sensitive assay for quantifying LRRK2 activity. Our work has implications for PD diagnosis, progression monitoring and therapeutic assessment.
Hypothesis: We hypothesize that we can use antibodies that bind to LRRK2, fused with a fragment of the light-emitting luciferase enzyme, to measure autophosphorylation of LRRK2 at residue S1292 and quantify LRRK2 activity in PD.
Study Design: We will begin by engineering parts of luciferase to produce light when LRRK2 becomes active. We will then determine whether this assay can detect S1292 phosphorylated LRRK2 in cells and samples from people with PD and we will assess its ability to diagnose PD and test the efficacy of PD treatments.
Impact on Diagnosis/Treatment of Parkinson’s disease: The development of this novel assay for quantifying LRRK2 activity could revolutionize PD diagnosis and treatment by enabling early detection, personalized therapeutic interventions and monitoring of treatment effectiveness, ultimately improving outcomes and quality of life for individuals with PD.
Next Steps for Development: If successful, the next steps would involve further validation of the assay in larger cohorts of people with PD and in clinical trials to assess its efficacy and accuracy in diagnosing PD and monitoring treatment response. Additionally, we would pursue collaboration with regulatory agencies to facilitate approval and integration of the assay into clinical practice.