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TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genes

ABSTRACT: Tuberous sclerosis complex (TSC) is an inherited neurodevelopmental (ND) disorder with frequent manifestations of epilepsy and autism spectrum disorder (ASD) caused by mutations in TSC1 or TSC2 genes. TSC1 and TSC2 form a complex inhibiting mechanistic target of rapamycin complex-1 (mTORC1) signaling, leading to hyperactive mTORC1 signaling upon TSC1/2 loss of function. Although rapalogs, which are FDA-approved allosteric mTORC1-selective inhibitors, are used to treat TSC-associated hamartomas, they are not effective for treating ND manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, whose activity is further modulated by the MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation in transcript-selective fashion depending on features in target mRNAs’ 5’ untranslated regions (5’UTRs), their effect on transcriptome-wide patterns of mRNA translation has not been compared. Here, employing CRISPR-modified, isogenic TSC2 patient-derived neural progenitor cells (NPCs), we examined how loss of TSC2 affects gene expression via changes in mRNA abundance and translation at a transcriptome-wide scale. This revealed abundant mRNA translation alterations in TSC2-Null NPCs overlapping with those we previously observed in TSC1-Null NPCs. Surprisingly, numerous non-monogenic ASD- and NDD-associated genes, identified in patients harboring putative loss-of-function mutations, were selectively translationally suppressed in TSC2-Null NPCs consistent with their distinct repertoire of 5’UTR features. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study thereby establishes mTORC1-eIF4F and MNK-eIF4E-sensitive mRNA translation as key components in TSC, ASD and other neurodevelopmental disorders; and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277844 | GEO | 2025/03/06

REPOSITORIES: GEO

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Project description:Tuberous sclerosis complex (TSC) is an inherited multi-system disorder caused by mutations in the TSC1 or TSC2 gene. TSC patients are often diagnosed with a range of neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD), intellectual disability (ID), anxiety and mood disorders. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) kinase signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using neural progenitor cells (NPCs) from patient-derived induced pluripotent stem cells (iPSCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in CRISPR-modified TSC1-null NPCs, which were unaffected by mTORC1 inhibition by rapamycin,the only approved therapy for TSC1. Here, to assess TSC1-dependent gene expression programs in NPCs, we used polysome-profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level. In addition to changes in mRNA abundance, this revealed numerous TSC1-dependent alterations in translational efficiencies. To assess the relevance of these gene expression alterations we performed polysome-profiling in post-mortem brains originating from ASD donors and matched controls. Strikingly, TSC1-dependent alterations in mRNA translation observed in NPCs were largely recapitulated in human brains. Furthermore, although polysome-profiling revealed a partial reversal of TSC1-associated gene expression alterations following rapamycin treatment, most genes related to neural activity/synaptic regulation or ASD that showed TSC1-dependent translation were rapamycin-insensitive. Therefore, we also examined whether early ND rapamycin-insensitive phenotypes in TSC1-null NPCs could be rescued by a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272 (Revolution Medicines, Inc.). Unlike rapamycin, RMC-6272 strongly inhibited translation and reversed TSC1-associated proliferation and neurite outgrowth phenotypes. In summary, we reveal ample translational alterations in TSC1 patient-derived NPCs recapitulating human brain expression profiles and potential implications for treatment of TAND.

Project description:DallePezze2012 - TSC-independent mTORC2 regulation This model is described in the article: A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K. Sci Signal 2012 Mar; 5(217): ra25 Abstract: The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2. By analyzing the effects of perturbations targeting several levels within the network in silico and experimentally, we found that, in contrast to current hypotheses, the TSC1-TSC2 complex was not a direct or indirect (acting through the negative feedback loop) regulator of mTORC2. Although mTORC2 activation required active PI3K, this was not affected by the negative feedback loop. Therefore, we propose an mTORC2 activation pathway through a PI3K variant that is insensitive to the negative feedback loop that regulates mTORC1. This putative pathway predicts that mTORC2 would be refractory to Akt, which inhibits TSC1-TSC2, and, indeed, we found that mTORC2 was insensitive to constitutive Akt activation in several cell types. Our results suggest that a previously unknown network structure connects mTORC2 to its upstream cues and clarifies which molecular connectors contribute to mTORC2 activation. This model is hosted on BioModels Database and identified by: BIOMD0000000581. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genes

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