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.
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.
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.
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.
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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.