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

M. Catarina Silva; Chialin Cheng; Waltraud Mair; Sandra Almeida; Helen Fong; M. Helal U. Biswas; Zhijun Zhang; Yadong Huang; Sally Temple; Giovanni Coppola; Daniel H. Geschwind; Anna Karydas; Bruce L. Miller; Kenneth S. Kosik; Fen-Biao Gao; Judith A. Steen; Stephen J. Haggarty

doi:10.1016/j.stemcr.2016.08.001

Stem Cell Reports (Sep 2016)

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

M. Catarina Silva,
Chialin Cheng,
Waltraud Mair,
Sandra Almeida,
Helen Fong,
M. Helal U. Biswas,
Zhijun Zhang,
Yadong Huang,
Sally Temple,
Giovanni Coppola,
Daniel H. Geschwind,
Anna Karydas,
Bruce L. Miller,
Kenneth S. Kosik,
Fen-Biao Gao,
Judith A. Steen,
Stephen J. Haggarty

Affiliations

M. Catarina Silva: Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Chialin Cheng: Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Waltraud Mair: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
Sandra Almeida: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Helen Fong: Departments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA
M. Helal U. Biswas: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Zhijun Zhang: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Yadong Huang: Departments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA
Sally Temple: Neural Stem Cell Institute, Regenerative Research Foundation, Rensselaer, NY 12144, USA
Giovanni Coppola: Departments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USA
Daniel H. Geschwind: Departments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USA
Anna Karydas: Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA
Bruce L. Miller: Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA
Kenneth S. Kosik: Department of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA
Fen-Biao Gao: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Judith A. Steen: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
Stephen J. Haggarty: Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

DOI: https://doi.org/10.1016/j.stemcr.2016.08.001
Journal volume & issue: Vol. 7, no. 3
pp. 325 – 340

Abstract

Read online

Frontotemporal 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.

Published in Stem Cell Reports

ISSN: 2213-6711 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.cell.com/stem-cell-reports/home

About the journal