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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents



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ID: 717320.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein
Authors:Ehrlich, M.; Hallmann, A. L.; Reinhardt, P.; Arauzo-Bravo, M. J.; Korr, S.; Ropke, A.; Psathaki, O. E.; Ehling, P.; Meuth, S. G.; Oblak, A. L.; Murrell, J. R.; Ghetti, B.; Zaehres, H.; Scholer, H. R.; Sterneckert, J.; Kuhlmann, T.; Hargus, G.
Date of Publication (YYYY-MM-DD):2015-07-14
Title of Journal:Stem Cell Reports
Volume:5
Issue / Number:1
Start Page:83
End Page:96
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany; DFG Research Center for Regenerative Therapies, Technische Universitat Dresden, 01307 Dresden, Germany. Max Planck Institute for Molecular Biomedicine, 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. Institute of Neuropathology, University Hospital Munster, 48149 Munster, Germany; Department of Neurology, University of Munster, 48149 Munster, Germany. Institute for Human Genetics, University of Munster, 48149 Munster, Germany. Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany. Department of Neurology, University of Munster, 48149 Munster, Germany. Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA. Institute of Neuropathology, University Hospital Munster, 48149 Munster, Germany. Max Planck Institute for Molecular Biomedicine, 48149 Munster, Germany; Institute of Neuropathology, University Hospital Munster, 48149 Munster, Germany. Electronic address: gunnar.hargus@ukmuenster.de.
Identifiers:ISSN:2213-6711 (Electronic) 2213-6711 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/26143746 [ID No:2]
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