Upregulation of GPR109A in Parkinson's disease

Abstract

Background: Anecdotal animal and human studies have implicated the symptomatic and neuroprotective roles of niacin in Parkinson's disease (PD). Niacin has a high affinity for GPR109A, an anti-inflammatory receptor. Niacin is also thought to be involved in the regulation of circadian rhythm. Here we evaluated the relationships among the receptor, niacin levels and EEG night-sleep in individuals with PD.

Methods and findings: GPR109A expression (blood and brain), niacin index (NAD-NADP ratio) and cytokine markers (blood) were analyzed. Measures of night-sleep function (EEG) and perceived sleep quality (questionnaire) were assessed. We observed significant up-regulation of GPR109A expression in the blood as well as in the substantia nigra (SN) in the PD group compared to age-matched controls. Confocal microscopy demonstrated co-localization of GPR109A staining with microglia in PD SN. Pro and anti-inflammatory cytokines did not show significant differences between the groups; however IL1-β, IL-4 and IL-7 showed an upward trend in PD. Time to sleep (sleep latency), EEG REM and sleep efficiency were different between PD and age-matched controls. Niacin levels were lower in PD and were associated with increased frequency of experiencing body pain and decreased duration of deep sleep.

Conclusions: The findings of associations among the GPR109A receptor, niacin levels and night-sleep function in individuals with PD are novel. Further studies are needed to understand the pathophysiological mechanisms of action of niacin, GPR109A expression and their associations with night-sleep function. It would be also crucial to study GPR109A expression in neurons, astrocytes, and microglia in PD. A clinical trial to determine the symptomatic and/or neuroprotective effect of niacin supplementation is warranted.

Figure 1. Illustration of the EEG sleep monitor.

Figure 2. GPR109A expression, NAD/NADH ratio and BHB levels in blood.

(A) Representative GPR109A western blots (B) GPR109A densitometry, (C) NAD/NADH ratio and (D) BHB levels. GPR109A expression and NAD/NADH ratio were tested in the WBCs. The BHB levels were tested in the sera. Young, n = 6; Older, n = 23, PD, n = 22. *p = 0.009 between Age-matched control and PD groups. **p = 0.033 between Age-matched control and PD groups. ^§ p = 0.071 between Age-matched control and PD groups.

Figure 3. A, Reduced Niacin index (NAD/NADP ratio) in RBCs and B, Total plasma metabolites by HPLC/MS.

A. NAD/NADP ratio was significantly reduced in the PD patients compared to age-matched controls (n = 18, p = 0.038). B. Total niacin metabolites from PD patient’s samples were significantly lower than that of their age-matched controls (p = 0.025). This data is in unison with our niacin factor (NAD/NDAP ratio) data.

Figure 4. Up-regulation of GPR109A in the substantia nigra of PD patients.

Figure 5. Co-localization of GPR109A and microglia in PD and control brain.

Confocal microscopy image of SN of human brain samples showing the glial marker, CD11b (green) co-localized with GPR109A (red). Control sample shows less microglia and GPR109A + cells. Note that all the GPR109+ cells are not co-localized with CD11b maker in control sample. Few neuronal Nuclei (blue) are seen.

Figure 6. Sleep in PD.

Sleep Efficiency, ratio of actual sleep divided by total attempted sleep. Actual Sleep, total duration spent sleeping (not including Wake and Time to Z). Total Attempted Sleep, from time to bed to morning rise. Times Woken, number of times subject awaken during night-sleep. Wake Duration, total duration of time spent awake during night-sleep. Light Sleep, light sleep stage. Deep Sleep, deep sleep stage. REM Sleep, rapid eye movement sleep stage. Time to Sleep, the time it takes to fall asleep (a.k.a. sleep latency). *p<0.05 between the PD and Older groups. (Young group's data are shown in order to visualize normative values.) Numbers are the effect sizes between the Older and PD groups, based on Cohen's d using averaged standard deviation .