Higher urate in LRRK2 mutation carriers resistant to Parkinson disease

Abstract

Objective: LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers. Methods: Banked plasma samples or urate levels were obtained for 3 cohorts of age-and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex. Results: Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p < 0.001), with similar results for separate assessments of women (p < 0.02) and men (p < 0.001). A 2 mg/dL increment in urate concentration decreased the odds of having PD by approximately 50% (odds ratio = 0.48, p = 0.004). Interpretation: These findings identify and substantiate urate as a biomarker of resistance to PD among LRRK2 mutation carriers.

LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

“…7A). Lower levels of purine nucleotide intermediates are especially notable in the context of PD: the plasma of PD patients (both LRRK2 mutant-associated and idiopathic) has been shown to contain significantly less hypoxanthine and uric acid levels (Johansen et al, 2009), and patients with higher plasma urate levels, despite carrying LRRK2 mutations, are less likely to develop PD (Bakshi et al, 2019). Indeed, urate is currently being investigated as a potential therapeutic of PD, highlighting the importance of purine biosynthesis.…”

Mitochondrial DNA Deletions Discriminate Affected from Unaffected LRRK2 Mutation Carriers

“…In a recently published article in the Annals of Neurology , Bakshi and colleagues determined the concentration of the antioxidant urate in serum samples from ~1,500 individuals with or without LRRK2 mutations that were affected or unaffected by Parkinson disease (PD) . In 3 independent cohorts, they detected significantly lower levels of urate in manifesting (LRRK2 + /PD + ) compared to nonmanifesting (LRRK2 + /PD − ) LRRK2 mutation carriers and speculated that the elevated PD risk in the LRRK2 + /PD + group may be due to increased LRRK2 activity, which can interfere with urate‐sensitive pathways including Nrf2 antioxidant signaling . There is evidence that Nrf2 counteracts mitochondrial damage by triggering the expression of mitochondrial transcription factor A (TFAM) .…”

LRRK2 regulates innate immune responses and neuroinflammation during Mycobacterium tuberculosis infection

“…(Johansen et al, 2009). Furthermore, LRRK2 mutation carriers with higher urate plasma levels are less likely to develop PD (Bakshi et al, 2019), and urate is currently being investigated as a potential therapeutic for PD. This highlights the importance of purine biosynthesis in the maintenance of healthy neurons.…”

“…Second, we propose that loss of LRRK2 contributes to type I IFN dysregulation through phosphorylation of the mitochondria-associated fission protein DRP1. Previous reports have shown that LRRK2 physically interacts with DRP1 and that LRRK2 mediates mitochondrial fragmentation through DRP1 (Bakshi et al, 2019). Overexpression of both wild-type LRRK2 and the G2019S mutant allele have been shown to cause mitochondrial fragmentation (X.…”