Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers.
OBJECTIVE: To test whether phosphorylated Ser-1292 LRRK2 levels in urine exosomes predicts LRRK2 mutation carriers (LRRK2+) and noncarriers (LRRK2-) with Parkinson disease (PD+) and without Parkinson disease (PD-). METHODS: LRRK2 protein was purified from urinary exosomes collected from participants in 2 independent cohorts. The first cohort included 14 men (LRRK2+/PD+, n = 7; LRRK2-/PD+, n = 4; LRRK2-/PD-, n = 3). The second cohort included 62 men (LRRK2-/PD-, n = 16; LRRK2+/PD-, n = 16; LRRK2+/PD+, n = 14; LRRK2-/PD+, n = 16). The ratio of Ser(P)-1292 LRRK2 to total LRRK2 was compared between LRRK2+/PD+ and LRRK2- in the first cohort and between LRRK2 G2019S carriers with and without PD in the second cohort. RESULTS: LRRK2+/PD+ had higher ratios of Ser(P)-1292 LRRK2 to total LRRK2 than LRRK2-/PD- (4.8-fold, p < 0.001) and LRRK2-/PD+ (4.6-fold, p < 0.001). Among mutation carriers, those with PD had higher Ser(P)-1292 LRRK2 to total LRRK2 than those without PD (2.2-fold, p < 0.001). Ser(P)-1292 LRRK2 levels predicted symptomatic from asymptomatic carriers with an area under the receiver operating characteristic curve of 0.844. CONCLUSION: Elevated ratio of phosphorylated Ser-1292 LRRK2 to total LRRK2 in urine exosomes predicted LRRK2 mutation status and PD risk among LRRK2 mutation carriers. Future studies may explore whether interventions that reduce this ratio may also reduce PD risk.
Fraser, KB; Moehle, MS; Alcalay, RN; West, AB; LRRK2 Cohort Consortium,
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