Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease

Abstract

Unlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD.

Keywords: Glucose metabolism; NADPH; Neurodegeneration; Parkinson's disease; Pentose-phosphate pathway.

Fig. 1

(A) Total nicotinamide adenine dinucleotide phosphate (NADPH) produced by the pentose phosphate pathway. The combined activity of G6PD and 6PGD is shown. One mU is defined as 1 μmole NADPH produced/min/unit of enzyme. Activity is shown as the mean NADPH produced per unit expressed per mg total protein ± SEM. (B) G6PD enzyme levels. Levels of the G6PD enzyme were measured by enzyme-linked immunosorbent assay (ELISA) and the combined total shown here per mg total protein. (C) Efficiency of G6PD. The efficiency of G6PD was calculated by expressing the total NADPH measured per mg total protein, per ELISA unit (U) of G6PD. Relative activities are shown as mean NADPH produced per ELISA unit of protein ± SEM. Levels are shown as mean ± SEM. Con- pathologically normal controls, n = 13. Mild-McKeith brainstem predominant Parkinson's disease (PD) cases n = 11. Mod/Sev-McKeith limbic and diffuse neocortical cases. PD cases n = 12. Alzheimer's disease (AD) Braak and Braak stages IV-VI n = 13. Gray-cortex Brodmann area 4. Black-putamen. White-cerebellar vermis. One-way analysis of variance (ANOVA) significance p < 0.05, with Bonferroni posttest versus control * p < 0.05, ** p < 0.01, *** p < 0.001. Abbreviations: AD, Alzheimer's disease; ANOVA, analysis of variance; ELISA, enzyme-linked immunosorbent assay; NADPH, nicotinamide adenine dinucleotide phosphate; PD, Parkinson's disease; SEM, standard error of the mean.