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Hippocampal gene expression in the GFAP-R237H rat model of Alexander disease at early and late stages of disease

ABSTRACT: Hippocampal gene expression in the GFAP-R237H rat model of Alexander disease at early and late stages of disease

PROVIDER: PRJNA1168136 | ENA |

REPOSITORIES: ENA

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Hippocampal gene expression in the GFAP-R237H rat model of Alexander disease at early and late stages of disease

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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Region specific astrocyte response to mutant GFAP in Alexander disease model mice during postnatal development.

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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.

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Region specific astrocyte response to mutant GFAP in Alexander disease model mice during postnatal development.

Project description:Gene expression analysis was performed in Gfap+/+, Gfap+/R236H, and mGFAPTg170-2 transgenic mice, using the Aldh1l1-eGFP-L10a transgenic line (JD130) to isolate translating ribosomes and purify astrocyte specific transcripts for RNAseq.

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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.

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

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