Dataset Information

Transcriptional Regulation by PHGDH Modulates Pathological Progression in a Human Brain Organoid Model of Late-Onset Alzheimer’s Disease

ABSTRACT: Phosphoglycerate Dehydrogenase (PHGDH), prominently expressed in brain astrocytes, exhibits heightened levels in the early stages of late-onset Alzheimer’s Disease (LOAD). We demonstrate that alterations in PHGDH expression within astrocytes in a human brain organoid model of LOAD induce pathological changes, independent of PHGDH’s canonical enzymatic role. Remarkably, PHGDH functions as a transcriptional regulator by binding to chromatin, as evidenced by ChIP-seq, snRNA-seq, knockdown, and mutation experiments. Our analysis identifies IKKa and HMGB1, regulators of NFκB and autophagy, as pivotal transcriptional targets of PHGDH. Dual knockdown of IKKa and HMGB1 in astrocytes effectively mitigates PHGDH-induced LOAD pathological changes in brain organoids, reducing Aβ aggregates, cell death, and NFκB activation while enhancing synaptic puncta and autophagy. These findings unveil a novel pathological pathway in LOAD, elucidating PHGDH’s role as a transcriptional regulator in disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261164 | GEO | 2025/07/02

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Experiment Overall Design: Total RNA samples were prepared from head tissues from 2 embryos of Phgdh knockout and littermate wild-type controls. Experiment Overall Design: RNA of 4 biological replicates was hybridized to Affymetrix Mouse Genome 430 2.0 arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

Dataset Information

Transcriptional Regulation by PHGDH Modulates Pathological Progression in a Human Brain Organoid Model of Late-Onset Alzheimer’s Disease

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets