Session Information
Date: Monday, September 23, 2019
Session Title: Gene and Cell-Based Therapies
Session Time: 1:45pm-3:15pm
Location: Les Muses Terrace, Level 3
Objective: To study alterations in urinary phospholipids as biomarkers of LRRK2 mutations and Parkinson’s disease (PD) status.
Background: LRRK2 mutations are a common cause of dominantly inherited PD. Previous studies showed decreases in urine levels of di-docohexaenoyl (22:6) bis(monacylglycrerol) phosphate (di-22:6-BMP) in LRRK2 knockout mice and in non-human primates treated with LRRK2 kinase inhibitors. We hypothesized that urine levels of BMP isoforms are higher among PD-causing gain-of-function mutation, LRRK2 G2019S.
Method: Using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), we analyzed 56 distinct species of bioactive phospholipids in urine from the LRRK2 Cohort Consortium (LCC, n=80). To confirm the key findings from the LCC samples, we analyzed urine from an independent Columbia University Irving Medical Center (CUMIC) LRRK2 Cohort (n=116) focusing on three BMP species. BMP levels were normalized to creatinine and compared across four groups (LRRK2 G2019S carriers and non-carriers with and without PD). Receiver Operating Characteristic (ROC) models were constructed to estimate the predictive value of urine BMP for PD status in the LRRK2 mutation carriers.
Results: In both cohorts, urine BMP isoforms (di-18:1-BMP, di-22:6BMP, 2,2’-di-22:6, 2,2’-di-18:1-BMP) were higher in G2019S carriers compared to non-carriers with and without PD (p<0.0001 for each isoform). Moreover, di-18:1-BMP levels were significantly higher in LRRK2 G2019S carriers with PD compared to those without PD in the CUIMC cohort (5.81 ng/mg of creatinine versus 3.43 ng/mg of creatinine; p=0.0495).
Conclusion: Urine BMP levels are strongly associated with LRRK2 mutation status, and modestly with PD status among G2019S carriers. These data support the importance of BMP in LRRK2 biology and the use of urinary BMP as a biomarker of LRRK2 activity in dose selection and patient enrichment.
To cite this abstract in AMA style:
R. Alcalay, F. Hsieh, S. Padmanabhan, M. Baptista, C. Kehow, S. Narayan, A. Boehme, K. Merchant. Increased level of a lysosomal phospholipid, BMP, in urine of LRRK2 G2019S mutation carriers with or without Parkinson’s disease: implications for therapeutic development [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/increased-level-of-a-lysosomal-phospholipid-bmp-in-urine-of-lrrk2-g2019s-mutation-carriers-with-or-without-parkinsons-disease-implications-for-therapeutic-development/. Accessed June 15, 2025.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/increased-level-of-a-lysosomal-phospholipid-bmp-in-urine-of-lrrk2-g2019s-mutation-carriers-with-or-without-parkinsons-disease-implications-for-therapeutic-development/