Alterations in the reduced pteridine contents in the cerebrospinal fluids of LRRK2 mutation carriers and patients with Parkinson’s disease

Abstract

Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase that is essential for the biosynthesis of dopamine. Parkinson's disease (PD) is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons, and biomarkers reflecting the degree of neurodegeneration are important not only for basic research but also for clinical diagnosis and the treatment of the disease. Although the total neopterin and biopterin levels in the cerebrospinal fluids (CSF) of the patients with PD were reported, alterations in the composition of reduced and oxidized forms of pteridine compounds have not been examined. In this study, we first examined the time-dependent alterations in BH4 and other reduced pteridine compounds in the CSF of an MPTP-treated monkey as a primate PD model. We found that the CSF levels of BH4 and dihydroneopterin, an intermittent metabolite of BH4-biosynthesis, altered inversely with progression of neurodegeneration, whereas those of dihydrobiopterin and neopterin were relatively low and constant. Next, we assayed the amounts of reduced pteridine compounds in the CSF of 36 pre-symptomatic LRRK2-mutation (N1437H or G2019S) carriers (LRRK2-carrier), 13 patients with PD symptoms (LRRK2-PD), 46 patients with sporadic PD (sPD), and 26 non-PD individuals. The BH4 levels were significantly lower in both the LRRK2-PD and sPD patients, and the LRRK2-carriers exhibited higher BH4 levels compared with the sPD patients. The total neopterin levels in the CSF of the LRRK2-PD were significantly higher than those in the sPD and non-PD individuals, which indicated greater inflammatory responses in the brains of LRRK2-PD patients. The present results suggest that detailed analyses of pteridine levels in the CSF might be useful for understanding the pathophysiology of familial PD and for monitoring PD progression.

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?

“…Biopterin was reported to be higher in LRRK2 PD than in sPD patients [81], and in an earlier study by the same investigators total biopterin was reported to be higher in LRRK2 PD [80]. (No results were presented in the latter study for the individual components of total biopterin.)…”

“…It was unclear if some of the samples were used in both studies. Conversely, although the studies on pteridines by Koshiba et al [80] and Ichinose et al [81] were both performed at the Tokyo Institute of Technology, different samples were used in the two studies. Koshiba et al used samples from carriers of the I2020T LRRK2 mutation, while Ichinose et al used carriers of the G2019S or N1437H LRRK2 mutations.)…”

“…Total neopterin did not differ significantly between sPD and LRRK2 PD patients. Ichinose et al [81], from the same institution, later compared CSF levels of tetrahydrobiopterin, dihydrobiopterin, biopterin, total biopterin, neopterin, dihydroneopterin, and total neopterin between the four diagnostic groups. Biopterin was lower in sPD than in LRRK2 CTL and LRRK2 PD subjects.…”

“…This was suggested by Koshiba et al [80], who theorized that the dopaminergic deficit in LRRK2 PD might be due to dysfunction rather than to degeneration of dopaminergic neurons. A conclusion of the study by Ichinose et al [81] was that because neopterin has been suggested to be a marker for activation of cell-mediated immunity, specifically microglial activation [172,173], increased levels of total neopterin in LRRK2 PD might indicate an elevated inflammatory response in the LRRK2 PD brain.…”

“…A power analysis for that study indicated a power of only 0.09 to detect a difference in group means of 2.7 ng/mL and a 0.66 probability of detecting a difference in group means of 10 ng/mL. Some studies did find analytes whose concentrations differed between the LRRK2 PD and LRRK2 CTL groups: 2-hydroxybutyrate (lower in LRRK2 PD than in LRRK2 CTL subjects [169]), mtDNA (higher in LRRK2 PD than in LRRK2 CTL subjects [78]), lamp2 (lower in female LRRK2 PD than in LRRK2 CTL subjects [141]), 8-ISO and 8-OHdG (both possibly lower in LRRK2 PD than in LRRK2 CTL subjects, as discussed below [127]), and total neopterin (higher in LRRK2 PD than in LRRK2 CTL in one study [81] but not in a second one [80]). The 24% decrease in LRRK2 PD vs. LRRK2 CTL subjects for tetrahydrobiopterin, examined only in the study by Ichinose et al [81], was not statistically significant, although it may be of biological rele-vance.…”