Study Rationale: Mutations in LRRK2 and GBA1 (which encodes the enzyme glucocerebrosidase, or GCase) are among the most common genetic risk factors for Parkinson’s disease (PD). Individuals with these mutations exhibit abnormally high levels of the lipid bis(monocylglycero)phosphate (BMP) in their urine. Understanding the biological significance of this clinical feature is important for establishing the use of BMP as PD biomarker. Our recent studies indicate that BMP is released in exosomes, membrane-enclosed vesicles secreted by cells. In this study, we will examine the role of LRRK2 and GCase in regulating the content and secretion of exosomes enriched in BMP.
Hypothesis: We hypothesize that changes in the activities of LRRK2 and GCase trigger release of BMP-enriched exosomes that contain disease-related cargos.
Study Design: Using cells derived from individuals with PD, we will investigate the impact of normal and pathogenic activities of LRRK2 and GCase in the secretion of BMP-enriched exosomes from endolysosomes (the cellular compartments in which exosomes are generated). In addition, we aim to purify BMP-enriched exosomes from urine samples of people with PD and examine their molecular content.
Impact on Diagnosis/Treatment of Parkinson’s disease: These studies will contribute to our current understanding of the mechanisms by which changes in LRRK2 and GCase activities contribute to PD pathology, and they will facilitate the use of exosomal BMP as diagnostic tool for PD.
Next Steps for Development: If successful, the proposed research will support future investigation and validation of BMP as a biomarker for PD. Use of exosomal BMP as a biomarker would facilitate diagnosis and therapeutic evaluation of people with PD.