RNA-binding activity of PHGDH drives amyloid-beta production in a human brain organoid model of sporadic Alzheimer's disease.

ABSTRACT: Pathological progression in sporadic Alzheimer's disease (sAD) initiates with an early rise in soluble amyloid-β (Aβ), preceding plaque formation and neurodegeneration. However, the molecular event triggering this initial accumulation remains unknown. We report that phosphoglycerate dehydrogenase (PHGDH), a consistent biomarker of prodromal sAD, drives Aβ production through a previously unrecognized RNA-binding function. Specifically, PHGDH binds the 3'UTR of EIF2AK1 mRNA, enabling the physical interaction between PHGDH and the EIF2AK1 protein. By facilitating the recruitment of EIF2AK1 to its substrate EIF2α, this complex drives EIF2α phosphorylation, thereby selectively promoting the translation of BACE1, the rate-limiting enzyme for Aβ generation. We demonstrate that PHGDH overex

SUBMITTER: Chen J 

PROVIDER: S-EPMC12933074 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature