Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA289973 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2103300_1.fastq.gz | Fastqsanger.gz | |||
| SRR2103300_2.fastq.gz | Fastqsanger.gz | |||
| SRR2103291_1.fastq.gz | Fastqsanger.gz | |||
| SRR2103291_2.fastq.gz | Fastqsanger.gz | |||
| SRR2103301_1.fastq.gz | Fastqsanger.gz |
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Project description:Deletions at 15q11.2 have been established to increase risk for multiple neurodevelopmental disorders (NDDs) including schizophrenia and epilepsy, yet show variable expressivity between individuals. To investigate the potential role of CYFIP1, a gene within the locus, we carried out knockdown experiments in human neural progenitor cells derived from 15q11.2 neutral induced pluripotent stem cells. Transcriptional profiling and cellular assays support a prominent role for CYFIP1 in cytoskeletal remodeling across all lines examined. Validating the utility of this model for study of disease, genes implicated in schizophrenia and epilepsy but not other disorders or traits unrelated to the deletion, were enriched among mRNAs dysregulated following knockdown. Importantly, and consistent with the variable expressivity of 15q11.2 deletions, the magnitude of disease-related effects varied between donor lines. Towards mechanisms, FMRP targets and synaptic genes were overrepresented among dysregulated mRNAs and as such may contribute to the schizophrenia and epilepsy effects we observe. Further model validation, and new candidate epilepsy genes, comes from machine-learning analyses showing a striking similarity between a subset of dysregulated transcripts and well-established epilepsy genes. Results provide support for an important contribution of CYFIP1 in 15q11.2 mediated risk for NDDs and demonstrate that disease-related biological signatures are evident prior to neuronal differentiation. This new human model of disease will be useful in identifying compounds that could ameliorate outcomes in deletion carriers.
2016-09-22 | GSE70935 | GEO
Project description:Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. Understanding timepoints of disturbances during neural cell differentiation processes could lead to an insight into the development of the disorder. In this context, human brain organoids and neural cells differentiated from patient-derived induced pluripotent stem cells are of great interest as a model to study the developmental origins of the disease. Here we evaluated the differential expression of proteins of schizophrenia patient-derived neural progenitors, early neurons, and brain organoids. Using bottom-up shotgun proteomics with a label-free approach for quantitative analysis. Multiple dysregulated proteins were found in pathways related to synapses, in line with postmortem tissue studies of schizophrenia patients. However, organoids and immature neurons exhibit impairments in pathways never before found in patient-derived induced pluripotent stem cell studies, such as spliceosomes and amino acid metabolism. In conclusion, here we provide comprehensive, large-scale, protein-level data that may uncover underlying mechanisms of the developmental origins of schizophrenia.
2023-03-11 | PXD026593 | Pride
Project description:Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. Understanding timepoints of disturbances during neural cell differentiation processes could lead to an insight into the development of the disorder. In this context, human brain organoids and neural cells differentiated from patient-derived induced pluripotent stem cells are of great interest as a model to study the developmental origins of the disease. Here we evaluated the differential expression of proteins of schizophrenia patient-derived neural progenitors, early neurons, and brain organoids. Using bottom-up shotgun proteomics with a label-free approach for quantitative analysis. Multiple dysregulated proteins were found in pathways related to synapses, in line with postmortem tissue studies of schizophrenia patients. However, organoids and immature neurons exhibit impairments in pathways never before found in patient-derived induced pluripotent stem cell studies, such as spliceosomes and amino acid metabolism. In conclusion, here we provide comprehensive, large-scale, protein-level data that may uncover underlying mechanisms of the developmental origins of schizophrenia.
2023-03-11 | PXD026381 | Pride
Project description:Transcriptome analysis of RNA samples collected from human control and FXS iPS cell-derived neural progenitors at day 1 and day 7 of differentiation Lack of fragile X mental retardation protein results in fragile X syndrome (FXS), which is the most common inherited intellectual disability syndrome and serves as an excellent model disease to study molecular mechanisms behind neuropsychiatric comorbidities. We compared the transcriptomes of human neural progenitors (NPCs) generated from patient-derived induced pluripotent stem cells (iPSCs) of three FXS and three control male donors. Altered expression of RAD51C, PPIL3, GUCY1A2, MYD88, TRAPPC4, LYNX1, and GTF2A1L in FXS NPCs suggested changes related to triplet repeat instability, RNA splicing, testes development, and pathways previously shown to be affected in FXS. LYNX1 is a cholinergic break of tissue plasminogen activator (tPA)-dependent plasticity, and its reduced expression was consistent with augmented tPA-dependent radial glial process growth in NPCs derived from FXS iPSC lines. An analysis of gene expression in LYNX1-related signaling pathways revealed that NPCs derived from an FXS male with concomitant epilepsy differed from the other FXS NPCs. The differently expressed genes comprised several epilepsy-related genes, including genes shown to cause the auditory epilepsy phenotype in the murine model of FXS. Functional enrichment analysis highlighted regulation of insulin-like growth factor pathway in human NPCs modeling FXS with epilepsy. Our results link early gene expression changes of FXS NPCs with the pathogenesis of FXS and comorbid epilepsy.
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2024-10-21 | GSE274303 | GEO
Project description:Understanding the molecular bases of neurological and psychiatric conditions is hampered by a lack of suitable patient-derived cellular models. The olfactory mucosa is a continually regenerating neural tissue that contains multipotent neural stem cells which are accessible and expandable in vitro as neurospheres. Here we demonstrate disease-specific differences in neurosphere-derived cell lines from patients with two unrelated neurological conditions. Lines derived from donors with schizophrenia exhibited significant dysregulation of neurodevelopmental pathways whereas those obtained from donors with Parkinson's disease demonstrated significant dysgregulation in mitochondrial function, oxidative stress and xenobiotic metabolism. Our model supports the hypothesis that diseases with multiple genetic and environmental risk factors are revealed in convergent cellular and molecular pathways in olfactory neurosphere-derived cells taken from patient cohorts. These patient-derived cells provide informative models that provide insights into neurobiological correlates of neurological and psychiatric disorders that may be useful for many neuropsychiatric/neurodegenerative conditions and for drug discovery
2010-06-04 | E-TABM-724 | biostudies-arrayexpress
Project description:Dysfunction of the thalamocortical pathway has been implicated in multiple psychiatric disorders, but mechanisms by which these defects emerge remain poorly understood. We explored this question in the context of the 22q11.2 microdeletion, which represents a significant genetic risk for schizophrenia, leveraging emerging technologies of in vitro brain organogenesis using chimeric brain organoids derived from human induced pluripotent stem cells. Here we show that the 22q11.2 microdeletion leads to transcriptional dysregulation in thalamic organoids that is enriched for psychiatric disease risk genes, including elevated expression of FOXP2, which represents the most significantly dysregulated transcription factor in glutamatergic neurons and astroctyes. In a co-culture model fusing thalamic and cortical organoids, we demonstrate that the 22q11.2 deletion mediates an overgrowth of thalamic axons via overexpression of FOXP2, which then subsequently mediates the overgrowth of reciprocal corticothalamic axons. Dysregulation of FOXP2 leads to downregulation of ROBO2, an axon repulsive receptor important for thalamocortical axon pathfinding, and knockdown of ROBO2 in control organoids phenocopies excessive outgrowth of thalamic axons. Together, our study suggests that early steps in thalamocortical pathway development may be dysregulated in a model of genetic risk for schizophrenia, and contribute to neural phenotypes in 22q11.2 microdeletion syndrome.
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2010-12-31 | E-GEOD-23703 | biostudies-arrayexpress
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2023-10-12 | E-MTAB-12634 | biostudies-arrayexpress
Project description:Transcriptome studies of brain resections from mesial temporal lobe epilepsy (mTLE) patients revealed a dysregulation of transforming growth factor (TGF)-β, interferon (IFN)-α/β and nuclear factor erythroid 2-related factor 2 (NRF2) pathways among other neuroinflammatory mechanisms. Since ubiquitin-specific proteases (USP), in particular USP15, have been shown to regulate these pathways, we hypothesized that the blockade of USP15 may provide therapeutic relief in treatment-resistant epilepsies. The intrahippocampal kainate mouse model for mTLE, an established model for pharmacoresistant epilepsy was used for validation of USP15 as a therapeutic target. Transgenic mice which constitutively lack USP15 underwent intrahippocampal kainate injections to investigate the impact of USP15 inactivation at the transcriptomic level.
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