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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents

ID: 744150.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
Astrocyte pathology in a human neural stem cell model of frontotemporal dementia caused by mutant TAU protein
Authors:Hallmann, A. L.; Arauzo-Bravo, M. J.; Mavrommatis, L.; Ehrlich, M.; Ropke, A.; Brockhaus, J.; Missler, M.; Sterneckert, J.; Scholer, H. R.; Kuhlmann, T.; Zaehres, H.; Hargus, G.
Date of Publication (YYYY-MM-DD):2017-03-03
Title of Journal:Sci Rep
Start Page:42991
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Astroglial pathology is seen in various neurodegenerative diseases including frontotemporal dementia (FTD), which can be caused by mutations in the gene encoding the microtubule-associated protein TAU (MAPT). Here, we applied a stem cell model of FTD to examine if FTD astrocytes carry an intrinsic propensity to degeneration and to determine if they can induce non-cell-autonomous effects in neighboring neurons. We utilized CRISPR/Cas9 genome editing in human induced pluripotent stem (iPS) cell-derived neural progenitor cells (NPCs) to repair the FTD-associated N279K MAPT mutation. While astrocytic differentiation was not impaired in FTD NPCs derived from one patient carrying the N279K MAPT mutation, FTD astrocytes appeared larger, expressed increased levels of 4R-TAU isoforms, demonstrated increased vulnerability to oxidative stress and elevated protein ubiquitination and exhibited disease-associated changes in transcriptome profiles when compared to astrocytes derived from one control individual and to the isogenic control. Interestingly, co-culture experiments with FTD astrocytes revealed increased oxidative stress and robust changes in whole genome expression in previously healthy neurons. Our study highlights the utility of iPS cell-derived NPCs to elucidate the role of astrocytes in the pathogenesis of FTD.
Free Keywords:Annexin A2/metabolism; Astrocytes/cytology/*metabolism/pathology; Cell Differentiation; Coculture Techniques; Frontotemporal Dementia/genetics/*pathology; Humans; Induced Pluripotent Stem Cells/cytology/metabolism; Models, Biological; Neural Stem Cells/cytology/metabolism; Neurons/cytology/metabolism; Oxidative Stress; Polymorphism, Single Nucleotide; Protein Isoforms/genetics; Transcriptome; Ubiquitination; tau Proteins/*genetics
External Publication Status:published
Document Type:Article
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Institute of Neuropathology, University Hospital Munster, 48149 Munster, Germany. Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastian, Spain. IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain. Ruhr-University Bochum, Medical Faculty, Department of Anatomy and Molecular Embryology, 44801 Bochum, Germany. Institute for Human Genetics, University of Munster, 48149 Munster, Germany. Institute of Anatomy and Molecular Neurobiology, Westfalische-Wilhelms University, 48149 Munster, Germany. DFG Research Center for Regenerative Therapies, Technische Universitat Dresden, 01307 Dresden, Germany. Westphalian Wilhelms University Munster; Medical Faculty, 48149 Munster, Germany. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.
Identifiers:ISSN:2045-2322 (Electronic) 2045-2322 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28256506 [ID No:2]
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