Abstract
Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to mutations in genes along the PI3K-mTOR pathway and the GATOR1 complex causes a spectrum of neurodevelopmental disorders (termed mTORopathies) associated with malformation of cortical development and intractable epilepsy. Despite these gene variants’ converging impact on mTORC1 activity, emerging findings suggest that these variants contribute to epilepsy through both mTORC1-dependent and -independent mechanisms. Here, we review the literature on in utero electroporation-based animal models of mTORopathies, which recapitulate the brain mosaic pattern of mTORC1 hyperactivity, and compare the effects of distinct PI3K-mTOR pathway and GATOR1 complex gene variants on cortical development and epilepsy. We report the outcomes on cortical pyramidal neuronal placement, morphology, and electrophysiological phenotypes, and discuss some of the converging and diverging mechanisms responsible for these alterations and their contribution to epileptogenesis. We also discuss potential therapeutic strategies for epilepsy, beyond mTORC1 inhibition with rapamycin or everolimus, that could offer personalized medicine based on the gene variant.
Highlights
MTORopathies comprise several neurodevelopmental disorders, including tuberous sclerosis complex (TSC), focal cortical dysplasia type II (FCDII), hemimegalencephaly (HME), and polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome, among others
The aim of this review is to examine neuronal molecular and functional alterations resulting from distinct phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) and GTPase-activating proteins (GAPs) activity toward Rags 1 (GATOR1) gene variants that converge on mechanistic target of rapamycin complex 1 (mTORC1) activation and discuss the potential mechanisms leading to epileptogenesis due to these pathological variants
We examine the activities of AKT-Glycogen synthase kinase 3 beta (GSK3β) on axon growth, AKT-Forkhead box G1 (FOXG1)-reelin on neuronal migration, and TSC/Ras homolog enriched in brain (RHEB)-mitogen-activated protein kinase (MAPK)/ERK-filamin A (FLNA) on neuronal dysmorphogenesis and seizures
Summary
MTORopathies comprise several neurodevelopmental disorders, including tuberous sclerosis complex (TSC), focal cortical dysplasia type II (FCDII), hemimegalencephaly (HME), and polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome, among others. We compare the outcomes of distinct PI3K-mTOR and GATOR1 gene variants on the structural alterations that are pathological hallmarks of TSC/FCDII, namely cell misplacement and neuronal hypertrophy. We discuss these findings in the context of major molecular processes downstream mTORC1 that have known contributions to these specific alterations, such as cap-dependent translation. In addition to PI3K-AKT signaling, recent studies have identified the GATOR1 complex, which consists of DEP domain containing 5 (DEPDC5) and the Nitrogen permease regulator 2-like (NRPL2) and 3-like (NPRL3) proteins, as a negative regulator of mTORC1 activity in response to cellular amino acid levels (Bar-Peled and Sabatini, 2014).
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