Graphical AbstractSchematic Representation Highlighting the Mechanisms of Nutrient Sensing and Autophagy Under Physiological Conditions.

Background: Parkinson's disease is the second most common neurodegenerative condition and has no cure. With the emergence of targeted treatments such as LRRK2 small molecule inhibitors that are currently being evaluated in clinical trials there is an urgent need for patient stratification and target engagement biomarkers. Urine BMP (didocohexaenoyl (22:6) bis(monoacylglycerol)phosphate) levels have previously been reported to be elevated in gain-of-kinase function LRRK2 G2019S mutation carriers and reduced in LRRK2 knockout mice, as well as non-human primates treated with LRRK2 kinase inhibitors. Objective: The purpose of this study was to independently validate and expand our understanding of urine BMPs as a PD biomarker in carriers of LRRK2 G2019S but also LRRK2 R1441 hotspot mutations, VPS35 D620N and GBA variants compared to idiopathic PD and control subjects. Methods: Up to 20 BMP species including total and 2,2'- isoforms of the di-18:1-BMP and di-22:6-BMP species were measured in urine from 106 participants: 22 controls, 31 with iPD, 10 with PD associated with GBA risk variants, as well as 18 LRRK2 G2019S, 13 LRRK2 R1441G/S and 10 VPS35 D620N mutation carriers either with or without PD. Results: Urine BMP levels were consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations, but not those carrying GBA risk variants. Conclusion: Urine BMP levels are attractive and promising biomarkers for patient stratification in PD and potentially target engagement in clinical trials. Our results further highlight the convergence of the LRRK2 and VPS35 signalling pathways.

Elevated urine bis(monoacylglycerol)phosphate (BMP) levels have been found in gain-of-kinase function LRRK2 G2019S mutation carriers. Here, we have expanded urine BMP analysis to other Parkinson’s disease (PD) associated mutations and found them to be consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations. Urine BMP levels are promising biomarkers for patient stratification and potentially target engagement in clinical trials of emerging targeted PD therapies.