The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration

Abstract

BackgroundMetabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson’s disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to glycolysis) converts glucose-6-phosphate into pentoses and generates ribose-5-phosphate and NADPH thereby governing anabolic biosynthesis and redox homeostasis. Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. However, spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. More importantly, it is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD.MethodsWe examined expression/activity of G6PD and its association with microglial activation and dopaminergic neurodegeneration in multiple chronic PD models generated by an intranigral/intraperitoneal injection of LPS, daily subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 6 days, or transgenic expression of A53T α-synuclein. Primary microglia were transfected with G6PD siRNAs and treated with lipopolysaccharide (LPS) to examine effects of G6PD knockdown on microglial activation and death of co-cultured neurons. LPS alone or with G6PD inhibitor(s) was administrated to mouse substantia nigra or midbrain neuron-glia cultures. While histological and biochemical analyses were conducted to examine microglial activation and dopaminergic neurodegeneration in vitro and in vivo, rotarod behavior test was performed to evaluate locomotor impairment in mice.ResultsExpression and activity of G6PD were elevated in LPS-treated midbrain neuron-glia cultures (an in vitro PD model) and the substantia nigra of four in vivo PD models. Such elevation was positively associated with microglial activation and dopaminergic neurodegeneration. Furthermore, inhibition of G6PD by 6-aminonicotinamide and dehydroepiandrosterone and knockdown of microglial G6PD attenuated LPS-elicited chronic dopaminergic neurodegeneration. Mechanistically, microglia with elevated G6PD activity/expression produced excessive NADPH and provided abundant substrate to over-activated NADPH oxidase (NOX2) leading to production of excessive reactive oxygen species (ROS). Knockdown and inhibition of G6PD ameliorated LPS-triggered production of ROS and activation of NF-кB thereby dampening microglial activation.ConclusionsOur findings indicated that G6PD-mediated PPP dysfunction and neuroinflammation exacerbated each other mediating chronic dopaminergic neurodegeneration and locomotor impairment. Insight into metabolic-inflammatory interface suggests that G6PD and NOX2 are potential therapeutic targets for PD.

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice

“…Therefore, only male mice were used in the present study. The reason for using smaller dose of LPS (2 mg/kg) compared with our previous studies (5 mg/kg) was because SNCA mice are more susceptible to LPS 27 and are used as a PD model 60 . Mice were euthanized 13 months later.…”

Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis

“…In contrast, E4FAD mice had enhanced TCA, PPP and bile acid metabolism compared to E3FAD mice. Both TCA and PPP pathways involve energy production through mitochondria [31]. Research shows that the PPP regulates the chronic neuroinflammation in the brain and may therapeutically improve neurodegeneration in the brain such as Parkinson's disease [31].…”

Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems

“…In turn, NADPH supplies electrons to NADPH oxidase (NOX), to generate ROS [42,45]. The blockage of glucose-6-phosphate dehydrogenase (G6PDH), which is the rate-limiting enzyme of the PPP, suppressed ROS production in LPS-stimulated mesencephalic neuron-glia cultures [48]. Thus, the functional heterogeneity of microglia is profoundly correlated with changes in energy metabolism.…”