Mental disorders, mortality following myocardial infarction, and the impact of the COVID-19 pandemic in England: a cohort study.

Germline heterozygous loss-of-function mutations in the phosphatase and tensin homolog () gene cause a spectrum of clinical manifestations known as hamartoma tumor syndrome (PHTS), which includes a high prevalence of neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, and epilepsy (–). A central mechanism underlying PHTS pathophysiology is the hyperactivation of the phosphoinositide 3-kinase (PI3K)-AKT-mTOR signaling pathway, a master regulator of cell growth, proliferation, and metabolism (). Consequently, inhibitors of mechanistic target of rapamycin (mTOR) such as rapamycin have been considered as therapeutic avenues (). However, clinical trials of mTOR inhibitors in patients with deficiency have yielded limited therapeutic benefits, likely due to the pathway’s broad physiological functions and the potential for both central and peripheral side effects (, ). These limitations underscore the need to identify more specific signaling effectors downstream of mTOR hyperactivation that directly contribute to neuropathology. The mTOR kinase serves as the catalytic core of two distinct complexes, mTORC1 and mTORC2 (, ). While the roles of these separate complexes have been studied extensively, their interplay in the context of -related NDDs has been less clear. Using human pluripotent stem cells (hPSCs) derived neural models that recapitulate key aspects of the human disorder, we previously demonstrated that synergistic hyperactivation of both mTORC1 and mTORC2 is required to drive the neural phenotypes observed in -deficient human neural precursors (NPs) and neurons, including hyperproliferation, cellular hypertrophy, and electrical hyperactivity (, ). Importantly, selective normalization of either mTORC1 or mTORC2, via genetic disruption of or , key components of each respective complex, was sufficient to prevent these abnormalities. These findings suggest that mTORC1 and mTORC2 converge on a common downstream effector or cellular process. Identifying this point of convergence is a critical next step toward developing more targeted therapeutics. A promising candidate for this convergence is the actin cytoskeleton, a dynamic network of filaments crucial for cell morphology, migration, and synaptic function. Dysregulation of the actin cytoskeleton is recognized as a significant contributor to the pathophysiology of various NDDs (). For instance, mutations in key actin-related genes, such as and (also known as ) are known to cause NDDs that share clinical manifestations with -related NDDs, including macrocephaly, intellectual disability, epilepsy, and autism spectrum disorders (–). Furthermore, altered neuronal actin content and dynamics have been mechanistically linked to other syndromic NDDs, including Fragile X syndrome, Tuberous Sclerosis, and Phelan-McDermid Syndrome (–). Both mTORC1 and mTORC2 have been independently shown to regulate actin dynamics. mTORC2, for example, is a well-established regulator of small GTPases such as RAC1, CDC24, and RHOA, which in turn control actin polymerization and cytoskeletal organization (–). mTORC1 has also been directly implicated in controlling cytoskeletal organization and filamentous actin (F-actin) content in neuronal contexts (–). Together, these insights raise the possibility that actin cytoskeleton may also contribute to the -deficient human neural cells, acting downstream of mTOR hyperactivation.