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Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease.

ABSTRACT: Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease.

PROVIDER: PRJNA1085641 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28270900_1.fastq.gz	Fastqsanger.gz
	SRR28270900_2.fastq.gz	Fastqsanger.gz
	SRR28270901_1.fastq.gz	Fastqsanger.gz
	SRR28270901_2.fastq.gz	Fastqsanger.gz
	SRR28264639_1.fastq.gz	Fastqsanger.gz

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Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease

Project description:Alexander disease (AxD) is a rare, severe neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein (GFAP). While the exact disease mechanism remains unknown, existing studies suggest that the mutant GFAP influences many cellular processes, including cytoskeleton stability, mechanosensing, cell energetics, and proteasome function. While most studies have primarily focused on GFAP-expressing astrocytes, this protein is also expressed by radial glia and neural progenitor cells, prompting questions about the impact of GFAP mutations on central nervous system (CNS) development. In this study, we present an intriguing observation of an impaired differentiation of astrocytes and neurons in co-cultures of astrocytes and neurons, as well as in brain organoids, both generated from patient-derived induced pluripotent stem (iPS) cells with a GFAP (R239C) mutation. Leveraging single-cell RNA sequencing (scRNA-seq), we identified distinct cell populations and transcriptomic changes between the GFAP mutant cells and an isogenic corrected control. These findings are supported with immunocytochemistry and proteomics. In co-cultures, the AxD mutation resulted in an increased abundance of immature cells, while in organoids, we observed an altered cell differentiation and reduced abundance of astrocytes. Additionally, gene expression analysis associated the AxD mutation with increased stress susceptibility, cytoskeletal abnormalities, and altered extracellular matrix and cell-cell communication patterns. Overall, our results suggest the possibility of a faulty differentiation in human iPS cell-derived models of AxD, opening new avenues for AxD research.

2024-09-09 | PXD048606 | Pride

Aberrant neurodevelopment in human iPS cell-derived neural organoid model of Alexander disease

Project description:Aberrant neurodevelopment in human iPS cell-derived neural organoid model of Alexander disease

| PRJNA1085644 | ENA

Aberrant neurodevelopment in human iPS cell-derived astrocyte-neuron co-culture model of Alexander disease

Project description:Aberrant neurodevelopment in human iPS cell-derived astrocyte-neuron co-culture model of Alexander disease

| PRJNA1085307 | ENA

Aberrant neurodevelopment in human iPS cell-derived neural organoid model of Alexander disease

Project description:3D-cultured unguided neural and cortical organoids derived from human iPS cells carrying a GFAP (R239C) mutation - an identified cause of Alexander disease (AxD) - and their isogenic controls were analyzed with scRNA-seq to investigate the effect of the GFAP mutation on brain development, cell type composition, and gene expression. Results of this analysis showed impaired astro- and neurogenesis in both types of organoids (unguided and cortical), including a lack of cells acquiring the astrocyte fate, and an increased abundance of cells differentiating into lineages other than neuroectodermal. The results also suggested dysregulation of extracellular matrix, membrane, and cytoskeleton components, which might have also affected their differentiation trajectories.

2024-04-07 | GSE261157 | GEO

Aberrant neurodevelopment in human iPS cell-derived astrocyte-neuron co-culture model of Alexander disease

Project description:Co-cultures of neurons and astrocytes derived from human iPS cells carrying a GFAP (R239C) mutation - an identified cause of Alexander disease (AxD) - were analyzed with single-cell RNA sequencing to assess cell population composition, differential gene expression, and cell-cell interaction differences in AxD co-cultures compared to controls. Oxygen-glucose deprivation (OGD) challenge was applied to identify differences in stress response. Our results suggested differentiation impairment especially in AxD astrocytes, represented by an enriched population of less differentiated cells and downregulation of mature astrocyte genes in AxD astrocytes-containing co-cultures. Furthermore, AxD co-cultures showed increased stress response represented by upregulation of metallothioneins and increased susceptibility to the OGD challenge.

2024-04-07 | GSE261110 | GEO

Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-04-07 | GSE261158 | GEO

Genetic modifiers of GFAP expression in mouse models of Alexander disease

Project description:Gene expression analysis was performed in mouse models with Alexander disease associated GFAP mutations

2023-01-17 | GSE197044 | GEO

Genetic modifiers of GFAP expression in mouse models of Alexander disease

Project description:Genetic modifiers of GFAP expression in mouse models of Alexander disease

| PRJNA808603 | ENA

Composition of Rosenthal fibers in Alexander disease patients and mouse models

Project description:Alexander disease (AxD) is a fatal neurodegenerative disorder characterized by the presence in astrocytes of protein aggregates called Rosenthal fibers (RFs). In this work, we used a new biochemical fractionation method to enrich for RFs followed by analysis of this fraction using quantitative iTRAQ mass spectrometry. This work identified 77 proteins not previously associated with RFs. Multiple proteins selected for follow-up were confirmed by immunobloting to be enriched in the RF fraction of both the AxD mouse models and human AxD patients including receptor for activated protein C kinase 1 (RACK1), G1/S-specific cyclin D2, and ATP-dependent RNA helicase DDX3X.

2016-05-23 | PXD002448 | Pride

KDM5C safeguards the appropriate timing of early neurodevelopment

Project description:We generated human induced pluripotent cells from intellectual disability patients carrying the c.2T>C mutation in KDM5C (Called “Mutant”). We generated a paired, isogenic human iPS cell line (called “Corrected”) using CRISPR/Cas9 and PiggyBac gene-editing technologies and conducted neuronal differentiation based on “Yichen Shi et al. Nat. Protoc. 7, 1836–1846 (2012)” to define differences in gene expression between the Mutant and Corrected during neurodevelopment.

2023-10-13 | E-MTAB-7551 | biostudies-arrayexpress

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