PHGDH-mediated serine synthesis in astrocytes supports neuroinflammation by sustaining NADH level to promote histone acetylation

Neuroinflammation contributes to the loss of dopamine neurons and motor dysfunctions in Parkinson's disease (PD). How cell metabolism regulates neuroinflammation by modulating epigenetic modifications is largely unknown. In this study, we found that the expression of phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first step of the de novo serine synthesis pathway was mainly expressed in astrocytes and l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) injection triggered the upregulation of PHGDH in astrocytes in substantia nigra. PHGDH inhibition or knockdown reduced proinflammatory cytokine production in primary astrocytes after LPS (lipopolysaccharide) stimulation which was not due to suppressed inflammatory signaling transduction. Mechanistically, PHGDH promotes proinflammatory cytokine transcription by sustaining nicotinamide adenine dinucleotide (NADH) accumulation to facilitate histone acetylation of cytokine promoters. Moreover, PHGDH inhibition-induced inflammatory response decreased neurotoxicity in vitro and alleviated astrocytes-mediated neuroinflammation and neurotoxicity in an MPTP mice model. This study reveals the role and mechanism of PHGDH-mediated serine synthesis in promoting the inflammatory response of astrocytes which may provide a potential target for neurological diseases involving neuroinflammation.