Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1281274 | ENA |
REPOSITORIES: ENA
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Project description:Tuberous sclerosis complex (TSC) is a rare genetic disease characterized by mTOR hyperfunction induced benign tumor growths in multiple organs and neurological symptoms. Because the molecular pathology is highly complex and the etiology poorly understood we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology. TSC2 deficient neural stem cells showed severely reduced neuronal functional maturation and characteristics of astrogliosis instead. Accordingly, transcriptome analysis uncovered an inflammatory response and increased metabolic activity, while ribosome profiling revealed excessive translation of ribosomal transcripts and higher synthesis rates of angiogenic growth factors. Treatment with mTOR inhibitors corrected translational alterations but not transcriptional dysfunction. These results extend our understanding of the molecular pathophysiology of TSC brain lesions, and suggest phenotype-tailored pharmacological treatment strategies. Rapamycin, AZD-8055, and DMSO were given to two TSC+/+ cell lines and two TSC-/- cell lines after six weeks of differentiation. Cells are harvested after 3 hours treatment and are subject to ribosome profiling and RNA-seq analysis.
2016-07-25 | E-GEOD-78960 | biostudies-arrayexpress
Project description:Tuberous Sclerosis Complex (TSC), an autosomal dominant condition, is engendered by heterozygous mutations in either TSC1 or TSC2 genes, manifesting in systemic growth of benign tumors. In addition to brain lesions, neurologic sequelae represent the greatest morbidity in TSC patients. Investigations utilizing TSC1/2-knockout animal or human stem cell models suggest that TSC deficiency-causing hyper-activation of mTOR signaling might precipitate anomalous neurodevelopmental processes. However, how the pathogenic variants of TSC1/2 genes identified in TSC patients affect the trajectory of human brain development and how they contribute to the neurological manifestations in TSC remain largely unexplored. Here, we employed 3-dimensional cortical organoids derived from induced pluripotent stem cells (iPSCs) from TSC patients harboring TSC2 mutations, alongside organoids from age- and sex-matched healthy individuals as controls. Through comprehensively longitudinal molecular and cellular analysis of TSC organoids, including transcriptomics and single cell transcriptomics, we found that TSC2 pathogenic variants led to dysregulated neurogenesis, synaptogenesis, and gliogenesis, particularly for reactive astrogliosis. The altered developmental trajectory of TSC organoids significantly resembles the molecular signatures of neuropsychiatric disorders, including autism spectrum disorders, epilepsy, and intellectual disability. Through cell-cell communication analysis at the single cell level, we identified that TSC2 pathogenic variants disrupted the cell-cell communications, in particular, neuron-astrocyte interactions within the NLGN-NRXN signaling network. Furthermore, cellular and electrophysiological assessments of TSC cortical organoids, along with proteomics and phosphoproteomics analyses of synaptosomes, revealed that pathogenic TSC2 variants precipitate perturbations in mitochondrial translational integrity, neurofilament formation, synaptic transmission, and neuronal network activity. Intriguingly, the increased neu
2024-11-22 | GSE247367 | GEO
Project description:Tuberous Sclerosis Complex (TSC), an autosomal dominant condition, is engendered by heterozygous mutations in either TSC1 or TSC2 genes, manifesting in systemic growth of benign tumors. In addition to brain lesions, neurologic sequelae represent the greatest morbidity in TSC patients. Investigations utilizing TSC1/2-knockout animal or human stem cell models suggest that TSC deficiency-causing hyper-activation of mTOR signaling might precipitate anomalous neurodevelopmental processes. However, how the pathogenic variants of TSC1/2 genes identified in TSC patients affect the trajectory of human brain development and how they contribute to the neurological manifestations in TSC remain largely unexplored. Here, we employed 3-dimensional cortical organoids derived from induced pluripotent stem cells (iPSCs) from TSC patients harboring TSC2 mutations, alongside organoids from age- and sex-matched healthy individuals as controls. Through comprehensively longitudinal molecular and cellular analysis of TSC organoids, including transcriptomics and single cell transcriptomics, we found that TSC2 pathogenic variants led to dysregulated neurogenesis, synaptogenesis, and gliogenesis, particularly for reactive astrogliosis. The altered developmental trajectory of TSC organoids significantly resembles the molecular signatures of neuropsychiatric disorders, including autism spectrum disorders, epilepsy, and intellectual disability. Through cell-cell communication analysis at the single cell level, we identified that TSC2 pathogenic variants disrupted the cell-cell communications, in particular, neuron-astrocyte interactions within the NLGN-NRXN signaling network. Furthermore, cellular and electrophysiological assessments of TSC cortical organoids, along with proteomics and phosphoproteomics analyses of synaptosomes, revealed that pathogenic TSC2 variants precipitate perturbations in mitochondrial translational integrity, neurofilament formation, synaptic transmission, and neuronal network activity. Intriguingly, the increased neu
2024-11-22 | GSE247368 | GEO
Project description:Tuberous sclerosis complex (TSC) is a rare genetic disease characterized by mTOR hyperfunction induced benign tumor growths in multiple organs and neurological symptoms. Because the molecular pathology is highly complex and the etiology poorly understood we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology. TSC2 deficient neural stem cells showed severely reduced neuronal functional maturation and characteristics of astrogliosis instead. Accordingly, transcriptome analysis uncovered an inflammatory response and increased metabolic activity, while ribosome profiling revealed excessive translation of ribosomal transcripts and higher synthesis rates of angiogenic growth factors. Treatment with mTOR inhibitors corrected translational alterations but not transcriptional dysfunction. These results extend our understanding of the molecular pathophysiology of TSC brain lesions, and suggest phenotype-tailored pharmacological treatment strategies. Two TSC+/- cell lines and two TSC-/- cell lines were independently generated from wild-type human embryonic stem cells by genome editting with zinc finger nucleases. Two cell lines were handled in the same way but without any known human gene editted and they are used as negative controls. Two independent biological replicates of each of the six cell lines are profiled with ribosome profiling technique.
2016-07-25 | E-GEOD-78959 | biostudies-arrayexpress
Project description:Primary murine neocortical cultures are a common model for investigating fundamental attributes of neuronal signalling. Here we utilized an Affymetrix GeneChip platform to measure expression of various genes in vitro in order to chracterize our cortical cultures.
2022-11-23 | GSE218028 | GEO
Project description:Treatment resistant epilepsy in tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mammalian target of rapamycin (mTOR) signaling. This can upregulate cell growth and proliferation, with increased downstream ribosomal S6 protein phosphorylation (phospho-S6). mTOR inhibitors are used in TSC, the archetypal mTORopathy, to reduce tumor growth or seizure frequency. Preclinical studies in FCD support a potential role in suppressing seizures. This pilot study sought to evaluate the safety of the mTOR inhibitor everolimus in treatment-resistant (failure of > 2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess changes in mTOR signaling and molecular pathways.
2021-12-10 | MSV000088551 | MassIVE
Project description:Tuberous Sclerosis Complex (TSC) is a disease caused by autosomal dominant mutations in the TSC1 or TSC2 genes, and is characterized by tumor susceptibility, brain lesions, seizures and behavioral impairments. The TSC1 and TSC2 genes encode proteins forming a complex (TSC), which is a major regulator and suppressor of mammalian target of rapamycin (mTOR) in complex 1 (mTORC1), a signaling complex that promotes cell growth and proliferation. TSC1/2 loss of heterozygosity (LOH) and the subsequent complete loss of TSC regulatory activity in null cells causes mTORC1 dysregulation and TSC-associated brain lesions or other tissue tumors. However, it is not clear whether TSC1/2 heterozygous brain cells are abnormal and contribute to TSC neuropathology. To investigate this issue, we generated induced pluripotent stem cells (iPSCs) from TSC patients and unaffected controls, and utilized these to obtain neural progenitor cells (NPCs) and differentiated neurons in vitro. These patient-derived TSC2 heterozygous NPCs were delayed in their ability to differentiate into neurons. Patient-derived progenitor cells also exhibited a modest activation of mTORC1 signaling downstream of TSC, and a marked attenuation of upstream PI3K/AKT signaling. We further show that pharmacologic AKT inhibition, but not mTORC1 inhibition, causes a neuronal differentiation delay, mimicking the patient phenotype. Together these data suggest that heterozygous TSC2 mutations disrupt neuronal development, potentially contributing to the disease neuropathology, and that this defect may result from dysregulated AKT signaling in neural progenitor cells.
2018-08-26 | GSE111584 | GEO
Project description:Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by heterozygous pathogenic variants in either TSC1 or TSC2. Emerging evidence suggests a connection between microglia activation and epilepsy as well as cognitive impairment in TSC patients. However, the impact of the causal variants of TSC1/2 genes on human microglia and their contribution to TSC's neurological symptoms remain largely unexplored. In this study, we generated human microglia from induced pluripotent stem cells (iPSCs) from a TSC patient cohort. Through extensive molecular and cellular analysis of TSC microglia, including transcriptomics, proteomics/phosphopreteomics, and lipidomics, we found that heterozygous TSC2 pathogenic variants were sufficient to cause aberrant lipid metabolism marked by increased glycerophosphocholines and fatty acyls. These metabolic changes resulted in enhanced phagocytosis and inflammation. Strikingly, the dysregulated lipid metabolism in TSC microglia is driven by a hyper-activated mTOR-lipoprotein lipase (LPL) pathway. Further, cellular and electrophysiological assessments of neuron/microglia co-cultures revealed that TSC microglia directly affect neuronal development, excitability, and neuronal network activity, which could be largely ameliorated by mTOR/LPL inhibition. Collectively, our research unveiled the molecular and cellular abnormalities in TSC microglia affecting neuronal development and function, and highlighted the mTOR-LPL pathway as a novel potential therapeutic target for the neuropathology of TSC.
2023-09-27 | GSE244091 | GEO