Year: 2024
Type: article
Abstract: Alexander disease (AxD) is a rare and severe neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP). While the exact disease mechanism remains unknown, previous studies suggest that mutant GFAP influences many cellular processes, including cytoskeleton stability, mechanosensing, metabolism, and proteasome function. While most studies have primarily focused on GFAP‐expressing astrocytes, GFAP 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 observed impaired differentiation of astrocytes and neurons in co‐cultures of astrocytes and neurons, as well as in neural organoids, both generated from AxD 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 differences between the mutant GFAP cultures and a corrected isogenic control. These findings were supported by results obtained with immunocytochemistry and proteomics. In co‐cultures, the GFAP R239C mutation resulted in an increased abundance of immature cells, while in unguided neural organoids and cortical organoids, we observed altered lineage commitment and reduced abundance of astrocytes. Gene expression analysis revealed increased stress susceptibility, cytoskeletal abnormalities, and altered extracellular matrix and cell–cell communication patterns in the AxD cultures, which also exhibited higher cell death after stress. Overall, our results point to altered cell differentiation in AxD patient‐derived iPS‐cell models, opening new avenues for AxD research.
Source: Glia
DOI: 10.1002/glia.24618
Institutions: Charles University, Czech Academy of Sciences, Institute of Biotechnology, Utrecht University, University Medical Center Utrecht, University of Gothenburg, Lund University, University of Zurich, University Children's Hospital Zurich, Oncode Institute, Centro de Investigaciones Biológicas Margarita Salas, Czech Academy of Sciences, Czech Academy of Sciences, Institute of Experimental Medicine, Florey Institute of Neuroscience and Mental Health, University of Newcastle Australia
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,190
Funders: “la Caixa” Foundation, Petrus och Augusta Hedlunds Stiftelse, Stiftelsen för Strategisk Forskning, Grantová Agentura České Republiky, ZonMw, Lunds Universitet, Svenska Sällskapet för Medicinsk Forskning, Hjärnfonden, Vetenskapsrådet, Stiftelsen för Strategisk Forskning, Oncode Institute, European Regional Development Fund, Agencia Estatal de Investigación
Awards: G1175115578, G1622782223, G1902886428, Constructing the Developmental Atlas of Alzheimer’s Disease using Cerebral Organoids and Single-Cell Transcriptomics, G2262748287, G300979063, G34346518, G3480869486, G355572793, G3751056395, G410571670, A humanized organoid-based platform for stroke modelling and mRNA-based therapeutic intervention, G425668148, G451917667, G4783582173, G5080475149, G5289763008, G5539308778, G5967599077, Astrocytes - a new target in stroke and neurodegeneration, G6971005425, G6980109441, G7084143925, Astrocytes - a novel target for neuroplasticity and CNS regeneration in stroke, neurotrauma and ALS, G8265045674, The astrocyte nanofilament system in Alexander disease – from molecules to function, uncovering new leads for therapy, G929308097
OpenAlex ID: W4402750352