Abstract
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of inherited Parkinson’s disease (PD). The most common PD-associated LRRK2 mutation, G2019S, induces increased production of reactive oxygen species in vitro. We therefore hypothesized that individuals with PD-associated LRRK2 mutations might have increased concentrations of oxidative stress markers and/or decreased total antioxidant capacity (TAC) in their cerebrospinal fluid (CSF). We measured two oxidative stress markers, namely 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO), and TAC in CSF from LRRK2 mutation-bearing PD patients (LRRK2 PD = 19), sporadic PD patients (sPD = 31), and healthy control subjects with or without these mutations (LRRK2 CTL = 30, CTL = 27). 8-OHdG and 8-ISO levels were increased in LRRK2 CTL subjects, while TAC was similar between groups. 8-ISO was negatively correlated, and TAC was positively correlated, with Montreal Cognitive Assessment scores in LRRK2 PD, LRRK2 CTL, and CTL subjects. Correlations in both groups of PD patients between the two oxidative stress markers and Unified Parkinson Disease Rating Scale Total scores were weak, while TAC was negatively correlated with these scores. These findings suggest that oxidative stress may be increased in the CNS in healthy individuals with PD-associated LRRK2 mutations. Further, TAC may decrease in the CNS with the progression of PD, and when cognitive impairment is present regardless of the presence or absence of PD.
Highlights
Parkinson’s disease (PD) is most commonly a sporadic disorder, but up to 10% of PD cases are associated with genetic mutations (Van Den Eeden et al, 2003)
The median concentrations of 8-OHdG in our groups were similar to those reported by Gmitterová et al (2009) and half to one-third of those reported by Kikuchi et al (2002); these latter two studies used ELISA to measure 8-OHdG, whereas Abe et al (2003) and Isobe et al (2010) employed HPLC
In contrast to the findings of Gmitterová et al (2009) discussed above, we found no evidence that cognitive deficits were associated with lower 8-OHdG levels in our PD patients
Summary
Parkinson’s disease (PD) is most commonly a sporadic disorder, but up to 10% of PD cases are associated with genetic mutations (Van Den Eeden et al, 2003). Expression of the most common PD-associated LRRK2 mutation, G2019S (Kachergus et al, 2005), may uncouple mitochondrial oxidative phosphorylation (Mortiboys et al, 2010; Papkovskaia et al, 2012) and increase intracellular ROS production in vitro (Pereira et al, 2014). These findings suggest that this LRRK2 mutation might increase CNS oxidative stress in healthy individuals, and/or contribute to oxidative stress in PD patients carrying this mutation. Because LRRK2’s binding to 14-3-3 controls its cellular localization, decrease in this binding results in cellular translocation of LRRK2, causing it to accumulate within cytoplasmic pools (Dzamko et al, 2010; Mamais et al, 2014)
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