Mutations in the LRRK2 and GBA genes increase the risk for Parkinson's disease (PD). The mechanism by which these mutations increase PD risk is unknown. One potential explanation may be that the activity of the enzymes (chemicals that increase chemical reactions) encoded by these genes is increased (as suspected in LRRK2) or reduced (as suspected in GBA). The purpose of this study is to collect tissue to measure, directly or indirectly, LRRK2 and GBA enzymatic quantity and activity. LRRK2 and its product, phosphorylated LRRK2, can be measured in the urine, and both LRRK2 and GBA can be measured in specially processed white blood cells (immune system cells) (peripheral blood mononuclear cell, or PBMCs). The goals of this project are to identify the best method to collect and store PBMCs and to store samples for future collaboration with laboratories interested in studying LRRK2 and GBA activity.
We hypothesize that GBA and LRRK2 quantity, enzymatic activity and products can be reliably measured in PBMCs. We hypothesize that GBA enzymatic activity is reduced in those who carry GBA mutations and increased in those who carry LRRK2 mutations.
We aim to collect urine samples and PBMCs from participants with and without LRRK2 or GBA mutations and with and without PD (total of 120 participants). We will ask participants to donate urine and blood samples, which will be specifically processed to isolate white blood cells (PBMCs). Samples will be stored at Columbia University and distributed to laboratories interested in developing assays (tests) to measure LRRK2 or GBA enzymatic activity. Samples will be shipped to Athens (Dr. Rideout) for PBMC processing to test GBA and LRRK2 quantity, activity and, in the case of LRRK2, quantity of products of the enzyme.
Impact on Diagnosis/Treatment of Parkinson's Disease:
This study aims to collect samples that will help scientists develop assays to measure LRRK2 activity. Quantifying LRRK2 activity is essential for the development of drugs that may modify or reduce the enzyme's activity. It also may help determine if drugs that aim to reduce enzymatic activity indeed reduce it.
Next Steps for Development:
If we can successfully collect urine and blood samples from mutation carriers and non-carriers, the next step is to establish collaborations with laboratories that would be interested in analyzing these samples for enzyme activity assay development.