Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex

Saber, Wardiya Afshar; Şahin, Mustafa

doi:10.1186/s13229-020-0320-2

Cited by 24 publications

(23 citation statements)

References 62 publications

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“…As a complement to these animal models, human stem cell-based models of TSC and other mTORopathies have emerged over recent years due to advances in human stem cell and genome engineering [164-168]. These systems can capture human- or patient-specific aspects of cell biology, genetics, and brain development and thus provide an important complement to mouse models.…”

Section: Animal Models Of Mtoropathiesmentioning

confidence: 99%

Current Approaches and Future Directions for the Treatment of mTORopathies

Karalis

Bateup

2021

Dev Neurosci

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The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.

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Section: Animal Models Of Mtoropathiesmentioning

confidence: 99%

Current Approaches and Future Directions for the Treatment of mTORopathies

Karalis

Bateup

2021

Dev Neurosci

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“…A few comprehensive overviews of human cell models with TSC1 and TSC2 knockouts in iPSCs, ESCs, and 3D organoid cultures were published recently [138,139]. Most studies are based on patient-specific iPSCs generated from TSC1 or TSC2 mutation carriers and indicate an overall decrease in neurons comparative to their respective controls [140][141][142][143].…”

Section: Cell Models Of Mtoropathies 411 Tscmentioning

confidence: 99%

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Vasić

Jones

Haslinger

et al. 2021

Genes

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Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.

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“…Cell specificity, mutation load, and mutation timing during brain development likely give rise to the diverse neuropathological presentations. Recent evidence from in vitro cell cultures and organoid models of TSC revealed that mTORC1 activity during cortical development is tightly controlled, and mTORC1 suppression is required for proper neurogenesis ( 51 ). Of note, mTORC1 hyperactivity promotes gliogenesis, likely explaining the increased number of glia in tubers ( 52 – 56 ).…”

Section: Introductionmentioning

confidence: 99%

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

et al. 2020

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Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.

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Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex

Cited by 24 publications

References 62 publications

Current Approaches and Future Directions for the Treatment of mTORopathies

Current Approaches and Future Directions for the Treatment of mTORopathies

Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

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