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PXD048606-2

PXD048606 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleAberrant neurodevelopment in human iPS cell-derived models of Alexander disease
DescriptionAlexander 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.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_06:57:48.650.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterCharlotte van Gelder
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListacetylated residue; monohydroxylated residue
InstrumentOrbitrap Exploris 480
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-01-16 07:59:59ID requested
12024-09-09 08:01:15announced
22024-10-22 06:57:49announced2024-10-22: Updated project metadata.
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: scRNA-seq,Alexander disease, GFAP, iPS cells, brain organoids
Contact List
Harmjan R Vos
contact affiliationOncode Institute and Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
contact emailh.r.vos-3@umcutrecht.nl
lab head
Charlotte van Gelder
contact affiliationUMC Utrecht
contact emailcharlottevangelder@gmail.com
dataset submitter
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Dataset FTP location
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