Objective: To determine whether plasma purine concentrations differ between people with Parkinson’s disease (PD) and matched controls among carriers of pathogenic mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) gene.

Background: LRRK2 mutations (mLRRK2) are the most common genetic cause of PD but are incompletely penetrant. Understanding the genetic and environmental factors that reduce LRRK2 mutation penetrance could help predict and possibly prevent development of PD among healthy people who are at high risk due to a mLRRK2. Urate is an endogenous purine with antioxidant, Nrf2 activator and neuroprotectant properties, and elevated serum or CSF concentrations are predictive of a reduced risk of idiopathic PD and a slower rate of PD progression.

Methods: Urate and other purines were measured in plasma samples by enzymatic and HPLC-UV/ECD assays. Baseline levels from 380 subjects (120 mLRRK2+PD-, 120 mLRRK2+PD+, 70 mLRRK2-PD-, 70 mLRRK2-PD+) matched for key covariates from the LRRK2 Cohort Consortium (LCC) and from 1,053 subjects (241 mLRRK2+PD-, 210 mLRRK2+PD+, 202 mLRRK2-PD-, 400 mLRRK2-PD+) in the Parkinson Progression Marker Initiative (PPMI) database were compared, adjusting for age and sex.

Results: Among mLRRK2 carriers in the LCC, unaffected subjects had higher levels of urate ± SE (5.0 ± 1.3 mg/dL) than those with PD (4.2 ± 1.2 mg/dL) by 0.8 mg/dL after adjusting for sex and age (p<0.0001). There was no significant difference between urate's purine precursors hypoxanthine and xanthine. A smaller difference was observed among subjects without a mLRRK2; plasma urate in unaffected subjects was 0.4 mg/dL greater than in PD (p=0.02). Similarly, among mLRRK2+ (in contrast to mLRRK2-) subjects in the PPMI cohort, those who were unaffected had higher levels of urate than those with PD (by 0.4 mg/dL) after adjusting for sex and age (p<0.001); adjusting further for BMI yielded the same result (p<0.001).

Conclusions: The reproducible finding of higher plasma urate levels among those resistant to PD despite a LRRK2 mutation supports the hypothesis that higher urate is a marker and possibly a mediator of the incomplete penetrance of LRRK2 mutations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/resistance-to-parkinsons-disease-among-lrrk2-mutation-carriers-is-associated-with-higher-plasma-levels-of-urate-but-not-its-purine-precursors/