ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation

Mutations in the phosphatase and tensin homolog (<i>PTEN</i>) gene are linked to severe neurodevelopmental disorders. Loss of <i>PTEN</i> causes hyperactivation of both mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2. Recent studies have shown that this dual hyperactivation is required for the neuropathology observed in <i>PTEN</i>-deficient human stem cell-derived neural cells. However, the molecular effectors that integrate these synergistic signals remain unknown. Here, we identify the actin-regulating ARP2/3 complex as a critical point of convergence downstream of mTORC1 and mTORC2. We show that concurrent hyperactivation of both complexes drives increased filamentous actin and elevated levels of the ARP2/3 complex subunits in <i>PTEN</i>-deficient human neural precursors (NPs) and neurons. Pharmacological or genetic inhibition of ARP2/3 is sufficient to rescue multiple disease-relevant phenotypes, including NP hyperproliferation, neuronal hypertrophy, and electrical hyperactivity, without affecting the upstream mTORC1 or mTORC2 hyperactivation. Together, these findings reveal the <i>PTEN</i>-mTOR-ARP2/3 signaling axis as a core mechanism of neuropathology and highlight ARP2/3 inhibition as a potential therapeutic strategy for <i>PTEN</i>-related neurodevelopmental disorders.