PHGDH-mediated serine synthesis reduces oligodendrocyte death by sustaining GSH and NADPH levels after brain ischemia

Introduction: White matter is vulnerable to early ischemic injury. The susceptibility of oligodendrocytes to ischemic damage can lead to demyelination, axonal degeneration, and neurological deficits, making them a key focus for understanding and developing therapies for stroke-related brain injury. In this study, we aimed to investigate how cell metabolism contributes to oligodendrocyte survival and white matter integrity maintenance following ischemia. Methods: NCT-503 was injected after inducing transient middle cerebral artery occlusion. After reperfusion, brain infarct volume and neurobehavioral deficits and behaviour performance were assessed. Immunofluorescence staining was performed to evaluate oligodendrocytes death. Cell viability was measured using the CCK8 assay. Flow cytometry analysis was conducted to examine reactive oxygen species (ROS) levels. Results: serine synthesis pathway enzyme phosphoglycerate dehydrogenase (PHGDH) was hardly expressed in neurons, microglia and oligodendrocyte precursor cells (OPCs) but selectively expressed in mature oligodendrocytes and astrocytes. Brain ischemic injury specifically enhanced the expression of PHGDH in oligodendrocytes. PHGDH inhibition with NCT-503 did not affect acute neuronal injury but worsened sensorimotor and cognitive functional outcomes after ischemic stroke. Moreover, white matter integrity and oligodendrocyte survival were specifically reduced after PHGDH inhibition and serine supplementation facilitated oligodendrocyte survival and enhanced white matter integrity, and consequently improved neurological functions. Mechanistically, PHGDH-mediated serine synthesis protected oligodendrocytes from oxidative stress-induced death by promoting glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) production through the one-carbon metabolism pathway. Conclusion: serine synthesis in reducing oligodendrocyte death which may provide a potential target for improving neurological function after ischemic stroke.