Deciphering the functional dichotomy of glucose 6 phosphate dehydrogenase in neuroinflammation for therapeutics development

Abstract

The glucose-6-phosphate dehydrogenase (G6PD) is a crucial enzyme for the pentose phosphate newlinepathway which plays a vital role in regulating the oxidative stress of many cell types. The newlinedeficiency primarily causes hemolytic anemia under oxidative stress triggered by food, drugs, or newlineinfection. Surprisingly, G6PD-deficient patients exhibited prolonged COVID-19 symptoms, newlineventilation support, neurological impacts, and high mortality. However, the mechanism of newlineCOVID-19 severity in G6PD deficient patients and its neurological manifestation is yet to be newlineelucidated. Besides, the role of G6PD-deficient microglia in neuroinflammation is still newlineambiguous. Here, using a CRISPR-edited G6PD deficient human microglia cell culture model, I newlineobserved a significant reduction in NADPH level and an increase in basal reactive oxygen species newline(ROS) in microglia. Interestingly, the deficiency of the G6PD-NAPDH axis impaired induced nitric newlineoxide synthase (iNOS) mediated nitric oxide (NO) production, which plays a fundamental role in newlineinhibiting viral replication. I also observed that the deficiency of the G6PD-NADPH axis reduced newlinelysosomal acidification, further abrogating the lysosomal clearance of viral particles. Thus, newlineimpairment of NO production, lysosomal functions, and redox dysregulation in G6PD deficient newlinemicroglia altered innate immune response, promoting the severity of SARS-CoV-2 pathogenesis. newlineHowever, the replenishment of NADPH is crucial for targeting G6PD deficiency-mediated newlinemicroglial dysfunctions. Therefore, my research also focuses on promoting alternate metabolic newlinepathways responsible for cytoplasmic NADPH production by targeting the expression and activity newlineof enzymes such as isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1). I observed that newlinemetabolites like citric and malic acid supplementation promote NADPH production and reduce newlinemicroglial oxidative stress. Additionally, the use of small-molecule nutraceuticals, such as newlinedieckol and resveratrol, enhances the expression of IDH1 and ME1 enzymes in microglia.