Mutations in the PTEN gene are linked to severe neurodevelopmental disorders. This study demonstrates that loss of PTEN results in the hyperactivation of two protein complexes, mTORC1 and mTORC2, leading to various disease-relevant phenotypes in human neurons, neural precursors, and cortical organoids. These phenotypes include hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. By generating double mutants of PTEN and components of mTORC1 or mTORC2, the study elucidates that the synergistic hyperactivation of both complexes is crucial for the observed neural phenotypes. These findings shed light on the molecular mechanisms underlying PTEN-related neural disorders and suggest potential therapeutic targets.

Keywords: Cortical organoids, synergistic hyperactivation, neural abnormalities