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Gene expression data from iPSC-derived astrocytes, comparison

ABSTRACT: Alexander disease (AxD) is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein (GFAP) as astrocytic inclusion. AxD is mainly caused by a gene mutation encoding GFAP, although the underlying pathomechanism remains unclear.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83374 | GEO | 2016/09/30

SECONDARY ACCESSION(S): PRJNA325729

REPOSITORIES: GEO

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Mutant GFAP alters lineage commitment of neural organoids [AxDorganoids_bulk_experiment2]

Project description:Glial fibrillary acidic protein (GFAP) is a type-3 intermediate filament protein mainly expressed in astrocytes in the central nervous system. Mutations in GFAP cause Alexander Disease (AxD), a rare and fatal neurological disorder. How exactly mutant GFAP eventually leads to white and grey matter deterioration in AxD remains unknown. GFAP is also expressed in radial glial cells, which are neural stem cells in the developing brain. Here, we used AxD patient-derived induced pluripotent stem cells (iPSCs) to explore the impact of mutant GFAP during neurodifferentiation. Our results show that GFAP is already expressed in iPSCs. Moreover, we have found that mutations in GFAP can severely affect neural organoid development through altering lineage commitment in embryoid bodies. Together, these results support a key role for GFAP as an early modulator of neurodevelopment.

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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.

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Project description:Alexander disease is a rare neurodegenerative disorder caused by mutations in the gene for glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes in the central nervous system. GFAP mutation causes a toxic gain-of-function and protein aggregation, ultimately leading to gliosis, astrocyte dysfunction, and neurodegeneration. To better understand the disease process, a rat model has been generated to mimic the common R239H mutation observed in the human disease (R237H in the rat). This study focuses on hippocampus, a brain region with a heavy burden of pathology, to determine the impact of GFAP mutation at presymptomatic (3 weeks of age) and severe stages ( 8 weeks of age) of disease. Transcription profiling shows progressive neuroinflammation and neurodegeneration.

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