title: Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein.
abstract: Frontotemporal dementia (FTD) is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein TAU. Because of limited availability of neural cells from patients' brains, the underlying mechanisms of neurodegeneration in FTD are poorly understood. Here, we derived induced pluripotent stem cells (iPSCs) from individuals with FTD-associated MAPT mutations and differentiated them into mature neurons. Patient iPSC-derived neurons demonstrated pronounced TAU pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD neurons showed an activation of the unfolded protein response, and a transcriptome analysis demonstrated distinct, disease-associated gene expression profiles. These findings indicate distinct neurodegenerative changes in FTD caused by mutant TAU and highlight the unique opportunity to use neurons differentiated from patient-specific iPSCs to identify potential targets for drug screening purposes and therapeutic intervention.
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Ehrlich
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Hallmann
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; DFG Research Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Reinhardt
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; 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: Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany; Department of Neurology, University of Münster, 48149 Münster, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Korr
authors.affiliation: Institute for Human Genetics, University of Münster, 48149 Münster, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Röpke
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Olympia E
authors.initials: OE
authors.lastname: Psathaki
authors.affiliation: Department of Neurology, University of Münster, 48149 Münster, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Ehling
authors.affiliation: Department of Neurology, University of Münster, 48149 Münster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Oblak
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Murrell
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Holm
authors.initials: H
authors.lastname: Zaehres
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.affiliation: Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; DFG Research Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Jared
authors.initials: J
authors.lastname: Sterneckert
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, 48149 Münster, Germany; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany. Electronic address: gunnar.hargus@ukmuenster.de.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Hargus
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D016501:Neurites / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D016875:tau Proteins