title: Astrocyte pathology in a human neural stem cell model of frontotemporal dementia caused by mutant TAU protein.
abstract: 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.
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, 48149 Münster, Germany.|Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Hallmann
authors.affiliation: Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastián, Spain.|IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, 48149 Münster, Germany.|Ruhr-University Bochum, Medical Faculty, Department of Anatomy and Molecular Embryology, 44801 Bochum, Germany.
authors.forename: Lampros
authors.initials: L
authors.lastname: Mavrommatis
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, 48149 Münster, Germany.|Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Ehrlich
authors.affiliation: Institute for Human Genetics, University of Münster, 48149 Münster, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Röpke
authors.affiliation: Institute of Anatomy and Molecular Neurobiology, Westfälische-Wilhelms University, 48149 Münster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Brockhaus
authors.affiliation: Institute of Anatomy and Molecular Neurobiology, Westfälische-Wilhelms University, 48149 Münster, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Missler
authors.affiliation: DFG Research Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Jared
authors.initials: J
authors.lastname: Sterneckert
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, 48149 Münster, Germany.|Westphalian Wilhelms University Münster; Medical Faculty, 48149 Münster, Germany.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.affiliation: Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, 48149 Münster, Germany.|Ruhr-University Bochum, Medical Faculty, Department of Anatomy and Molecular Embryology, 44801 Bochum, Germany.
authors.forename: Holm
authors.initials: H
authors.lastname: Zaehres
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, 48149 Münster, Germany.|Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Hargus
mesh_terms: D017306:Annexin A2 / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D018920:Coculture Techniques; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D059467:Transcriptome; D054875:Ubiquitination; D016875:tau Proteins / Q000235:genetics*
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D020033:Protein Isoforms; D016875:tau Proteins