Synergistic hyperactivation of both mTORC1 and mTORC2 underlies the neural abnormalities of PTEN-deficient human neurons and cortical organoids

Cell Rep. 2024 May 28;43(5):114173. doi: 10.1016/j.celrep.2024.114173. Epub 2024 May 2.

Abstract

Mutations in the phosphatase and tensin homolog (PTEN) gene are associated with severe neurodevelopmental disorders. Loss of PTEN leads to hyperactivation of the mechanistic target of rapamycin (mTOR), which functions in two distinct protein complexes, mTORC1 and mTORC2. The downstream signaling mechanisms that contribute to PTEN mutant phenotypes are not well delineated. Here, we show that pluripotent stem cell-derived PTEN mutant human neurons, neural precursors, and cortical organoids recapitulate disease-relevant phenotypes, including hypertrophy, electrical hyperactivity, enhanced proliferation, and structural overgrowth. PTEN loss leads to simultaneous hyperactivation of mTORC1 and mTORC2. We dissect the contribution of mTORC1 and mTORC2 by generating double mutants of PTEN and RPTOR or RICTOR, respectively. Our results reveal that the synergistic hyperactivation of both mTORC1 and mTORC2 is essential for the PTEN mutant human neural phenotypes. Together, our findings provide insights into the molecular mechanisms that underlie PTEN-related neural disorders and highlight novel therapeutic targets.

Keywords: CP: Cell biology; CP: Neuroscience; PTEN; autism; brain organoids; epilepsy; mTOR; neurodevelopmental disorders; neurons.

MeSH terms

  • Cell Proliferation
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Humans
  • Mechanistic Target of Rapamycin Complex 1* / metabolism
  • Mechanistic Target of Rapamycin Complex 2* / metabolism
  • Mutation / genetics
  • Neurons* / metabolism
  • Organoids* / metabolism
  • PTEN Phosphohydrolase* / genetics
  • PTEN Phosphohydrolase* / metabolism
  • Phenotype
  • Rapamycin-Insensitive Companion of mTOR Protein / genetics
  • Rapamycin-Insensitive Companion of mTOR Protein / metabolism
  • Regulatory-Associated Protein of mTOR / genetics
  • Regulatory-Associated Protein of mTOR / metabolism
  • Signal Transduction

Substances

  • PTEN Phosphohydrolase
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • PTEN protein, human
  • Rapamycin-Insensitive Companion of mTOR Protein
  • RICTOR protein, human
  • Regulatory-Associated Protein of mTOR
  • RPTOR protein, human