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.
Highlights
Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson’s disease (PD)
Sustained high activity of the Pentose phosphate pathway (PPP) in PD models To investigate the role of the PPP in PD, we first detected expression and activity of glucose-6-phosphate dehydrogenase (G6PD), the ratelimiting enzyme of the PPP, in four in vivo mouse PD models generated by an intranigral or intraperitoneal injection of LPS, daily subcutaneous injection of MPTP for 6 days, or transgenic overexpression of A53T mutant α-synuclein
The present study has demonstrated that aberrant upregulation of G6PD in microglia exacerbated LPSinduced chronic neurodegeneration through amplifying cellular oxidative stress and inflammatory response
Summary
Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson’s disease (PD). Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the ratelimiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. Spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. It is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD. Parkinson’s disease (PD), the most common age-related neurodegenerative movement disorder, is characterized by progressive loss of dopamine (DA) neurons in the substantia nigra (SN) [1]. Emerging evidence has uncovered important roles of metabolic and inflammatory dysregulation in PD pathogenesis [2,3,4,5]. To discern mechanism(s) flipping neuroinflammation from a beneficial physiological response to a chronic neurodegenerative one is urgent and of paramount importance
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