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Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

dc.contributor.authorM. Catarina Silva
dc.contributor.authorChialin Cheng
dc.contributor.authorWaltraud Mair
dc.contributor.authorSandra Almeida
dc.contributor.authorHelen Fong
dc.contributor.authorM. Helal U. Biswas
dc.contributor.authorZhijun Zhang
dc.contributor.authorYadong Huang
dc.contributor.authorSally Temple
dc.contributor.authorGiovanni Coppola
dc.contributor.authorDaniel H. Geschwind
dc.contributor.authorAnna Karydas
dc.contributor.authorBruce L. Miller
dc.contributor.authorKenneth S. Kosik
dc.contributor.authorFen-Biao Gao
dc.contributor.authorJudith A. Steen
dc.contributor.authorStephen J. Haggarty
dc.contributor.otherDepartment of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
dc.contributor.otherDepartment of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
dc.contributor.otherDepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
dc.contributor.otherDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
dc.contributor.otherDepartments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA
dc.contributor.otherDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
dc.contributor.otherDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
dc.contributor.otherDepartments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA
dc.contributor.otherNeural Stem Cell Institute, Regenerative Research Foundation, Rensselaer, NY 12144, USA
dc.contributor.otherDepartments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USA
dc.contributor.otherDepartments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USA
dc.contributor.otherDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA
dc.contributor.otherDepartment of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA
dc.contributor.otherDepartment of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA
dc.contributor.otherDepartment of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
dc.contributor.otherDepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
dc.contributor.otherDepartment of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
dc.date.accessioned2016-09-15T11:30:08Z
dc.date.available2025-10-02T03:11:47Z
dc.date.issued01-09-2016
dc.identifier.issn-
dc.identifier.urihttp://www.sciencedirect.com/science/article/pii/S2213671116301515
dc.description.abstractFrontotemporal dementia (FTD) and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC)-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.
dc.format-
dc.language.isoEN
dc.publisherElsevier
dc.relation.uri['https://journals.viamedica.pl/oncology_in_clinical_practice/about/customPage/aboutPlugin-page-407?adapted=1#aboutPlugin-page-407', 'https://journals.viamedica.pl/oncology_in_clinical_practice/about/submissions#authorGuidelines', 'https://journals.viamedica.pl/oncology_in_clinical_practice']
dc.rightsCC BY-NC-ND
dc.subject['oncology', 'cancer', 'neoplastic', 'chemotherapy', 'radiotherapy', 'radiation oncology', 'Neoplasms. Tumors. Oncology. Including cancer and carcinogens', 'RC254-282']
dc.subject.lccMedicine (General)
dc.titleHuman iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability
dc.typeArticle
dc.description.pages325-340
dc.description.doi10.1016/j.stemcr.2016.08.001
dc.title.journalStem Cell Reports
dc.identifier.e-issn-
dc.identifier.oaioai:doaj.org/journal:10da84fde5194cf7a648c0db3a201ba1
dc.journal.infoVolume 7, Issue 3


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