Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease

Background: Pathogenic leucine-rich repeat kinase 2 LRRK2 mutations may increase LRRK2 kinase activity and Rab substrate phosphorylation. Genetic association studies link variation in LRRK2 to idiopathic Parkinson disease (iPD) risk. Objectives: Through measurements of the LRRK2 kinase substrate pT73-Rab10 in urinary extracellular vesicles, this study seeks to understand how LRRK2 kinase activity might change with iPD progression. Methods: Using an immunoblotting approach validated in LRRK2 transgenic mice, the ratio of pT73-Rab10 to total Rab10 protein was measured in extracellular vesicles from a cross-section of G2019S LRRK2 mutation carriers (N = 45 participants) as well as 485 urine samples from a novel longitudinal cohort of iPD and controls (N = 85 participants). Generalized estimating equations were used to conduct analyses with commonly used clinical scales. Results: Although the G2019S LRRK2 mutation did not increase pT73-Rab10 levels, the ratio of pT73-Rab10 to total Rab10 nominally increased over baseline in iPD urine vesicle samples with time, but did not increase in age-matched controls (1.34-fold vs. 1.05-fold, 95% confidence interval [CI], 0.004–0.56; P = 0.046; Welch's t test). Effect estimates adjusting for sex, age, disease duration, diagnosis, and baseline clinical scores identified increasing total Movement Disorder Society-Sponsored Revision of the Unified (MDS-UPDRS) scores (β = 0.77; CI, 0.52–1.01; P = 0.0001) with each fold increase of pT73-Rab10 to total Rab10. Lower Montreal Cognitive Assessment (MoCA) score in iPD is also associated with increased pT73-Rab10. Conclusions: These results provide initial insights into peripheral LRRK2-dependent Rab phosphorylation, measured in biobanked urine, where higher levels of pT73-Rab10 are associated with worse disease progression.