Increased Oxidative Stress Markers in Cerebrospinal Fluid from Healthy Subjects with Parkinson’s Disease-Associated LRRK2 Gene Mutations

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.

What Have We Learned from Cerebrospinal Fluid Studies about Biomarkers for Detecting LRRK2 Parkinson’s Disease Patients and Healthy Subjects with Parkinson’s-Associated LRRK2 Mutations?

“…The same pattern may hold for dihydrobiopterin, neopterin, and dihydroneopterin. Because biopterin is the fully oxidized form of tetrahydrobiopterin, the finding of an increased biopterin concentration in LRRK2 PD CSF suggests that CNS oxidative stress may be greater in LRRK2 PD than in sPD, although this was not supported by the findings in the study by Loeffler et al [127] which assessed different measures of oxidative stress (8-OHdG, 8-ISO, and TAC). An alternative explanation for the higher biopterin concentration in LRRK2 PD than in sPD CSF is that because approximately 80% of CSF biopterin is produced by nigrostriatal dopaminergic neurons [171], lower CSF biopterin in sPD patients might indicate that loss of dopaminergic neurons in sPD is more extensive in sPD than in LRRK2 PD.…”

“…Loeffler et al [125] found no differences between the four diagnostic groups for CSF concentrations of nuclear factor (erythroidderived 2)-like 2 (Nrf2), a major regulator of the anti-oxidant response [126], although Nrf2 levels were positively associated with total and part III (motor) UPDRS scores for LRRK2 PD patients. The same investigators subsequently compared CSF levels of 8-OHdG, 8-isoprostane (8-ISO), and total antioxidant capacity (TAC), between the four diagnostic groups [127]. 8-OHdG is a marker for oxidative damage to nuclear and mitochondrial DNA [128] and 8-ISO is a marker for peroxidation of arachidonic acid [129].…”

Neuroprotective Mechanisms of Three Natural Antioxidants on a Rat Model of Parkinson’s Disease: A Comparative Study

“…Whilst the etiology of PD remains unclear so far, numerous reports suggest a connection between OS and the pathogenesis of the disease [78,79]. One of the concepts of PD pathogenesis focuses on the formation of ROS and the role of oxidative stress leading to damage of SNPC neurons.…”

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

“…The 14‐3‐3 proteins are a highly conserved family of proteins found throughout the evolutionary scale and are implicated in many cellular functions, notably, they act to promote cell survival through inhibition of many known proapoptotic factors including the mitochondrial Bcl‐2 family member BAD and the transcription factor Forkhead (Yuan & Yankner, ). The 14‐3‐3 proteins bind to serine/threonine‐phosphorylated residues, often functioning as direct regulators of the target proteins to which they bind (Loeffler, Klaver, Coffey, Aasly, & LeWitt, ). Seven isoforms are described in mammals.…”