Gene expression changes associated with Alexander disease (AxD)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116327 | GEO | 2018/08/01
REPOSITORIES: GEO
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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
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:Gene expression changes associated with Alexander disease (AxD)
| PRJNA478185 | ENA
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.
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Project description:The goals of this study are to generate inflammation-sensitive astrocytes from human induced pluripotent stem cells. We examine the transcriptomic inflammatory signature of generated astrocytes following Il1Beta exposure. Primary human cerebellar astrocytes, human induced pluripotent stem cells (hiPSC)-derived neural precursor cells (NPCs) and hiPSC-derived astrocytes were treated with Il1beta and compared to vehicle treated controls. Results: hiPSC-derived can be differentiated to astrocytes that are inflammation sensitive.
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Project description:In this work we used our zebrafish model of Alexander Desease (AxD), aiming at unraveling the main pathways involved in AxD pathogenesis performing the first multi-omics analysis on a in vivo model of AxD. The obtained results have been functionally validated and they open the way to further investigation about the involvement of metabolic processes in AxD.
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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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Project description:Advancements in human induced pluripotent stem cell (hiPSC) technology have enabled co-culture models for disease modeling in physiologically relevant systems. However, co-culturing protocols face challenges in usability and consistency. Here, we introduce a robust, reproducible hiPSC-derived co-culture system integrating astrocytes, neurons, and microglia. This model leverages cryopreserved cells, enabling co-cultures within 20 days post-thaw. Comparing monocultures and tri-cultures, we show how cell-cell interactions shape transcriptional and functional states across all three cell types. Neurons in tri-culture exhibit increased spine density and activity, while astrocytes and microglia show altered responses to proinflammatory stimulation. Surprisingly, astrocyte co-culture induces upregulation of disease-associated microglia (DAM) genes, including TREM2, SPP1, APOE, and GPNMB. Additionally, while familial Alzheimer’s disease neurons induce a prototypical inflammatory response in microglia, the DAM signature is significantly downregulated. Collectively, this study establishes a versatile human tri-culture model as a valuable resource for dissecting neuron-glia interactions and their role in neurodegenerative disease.
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Project description:Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. Using this method, we generated hiPSC-derived astrocyte populations (hiPSC-astrocytes) from 42 NPC lines (derived from 30 individuals) with an average of ~90% S100β-positive cells. Transcriptomic analysis demonstrated that the hiPSC-astrocytes are highly similar to primary human fetal astrocytes and characteristic of a non-reactive state. hiPSC-astrocytes respond to inflammatory stimulants, display phagocytic capacity and enhance microglial phagocytosis. hiPSC-astrocytes also possess spontaneous calcium transient activity. Our novel protocol is a reproducible, straightforward (single media) and rapid (<30 days) method to generate homogenous populations of hiPSC-astrocytes that can be used for neuron-astrocyte and microglia-astrocyte co-cultures for the study of neuropsychiatric disorders.
2017-08-18 | GSE97904 | GEO
Project description:Microglia play crucial roles in mediating neuronal homeostasis but have been implicated in contributing to amyotrophic lateral sclerosis (ALS). However, the role of microglia in ALS remains incompletely understood. Here, we generated highly enriched cultures of VCP mutant microglia derived from human induced pluripotent stem cells (hiPSCs) to investigate their cell autonomous and non-cell autonomous roles in ALS pathogenesis. We used RNA-sequencing, proteomics and functional assays to study hiPSC derived VCP mutant microglia and their effects on hiPSC derived motor neurons and astrocytes. Transcriptomic, proteomic and functional analyses revealed immune and lysosomal dysfunction in VCP mutant microglia. Stimulating healthy microglia with inflammatory inducer lipopolysaccharide (LPS) showed partial overlap with VCP mutant microglia in their reactive transformation. LPS-stimulated VCP mutant microglia displayed differential activation of inflammatory pathways compared with LPS-stimulated healthy microglia. Conserved gene expression changes were identified between VCP mutant microglia, SOD1 mutant mice microglia, and postmortem ALS spinal cord microglial signatures, including increased expression of the transmembrane glycoprotein GPNMB. While knockdown of GPNMB affected inflammatory and phagocytosis processes in microglia, this was not sufficient to ameliorate cell autonomous phenotypes in VCP mutant microglia. Secreted factors from VCP mutant microglia were sufficient to activate the JAK-STAT pathway in hiPSC derived motor neurons and astrocytes. VCP mutant microglia undergo cell autonomous reactive transformation involving immune and lysosomal dysfunction that partially recapitulate key phenotypes of microglia from ALS models and post mortem tissue and are independent of GPNMB. VCP mutant microglia elicit non cell autonomous responses in motor neurons and astrocytes involving the JAK-STAT pathway.
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