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Stem Cell Reports. 2016 Sep 13;7(3):325-340. doi: 10.1016/j.stemcr.2016.08.001. Epub 2016 Sep 1.

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

Author information

1
Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
2
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
4
Departments of Neurology and Pathology, Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA.
5
Neural Stem Cell Institute, Regenerative Research Foundation, Rensselaer, NY 12144, USA.
6
Departments of Neurology and Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024, USA.
7
Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA 94158, USA.
8
Department of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA.
9
Department of Neurology, Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: shaggarty@mgh.harvard.edu.

Abstract

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.

PMID:
27594585
PMCID:
PMC5032560
DOI:
10.1016/j.stemcr.2016.08.001
[Indexed for MEDLINE]
Free PMC Article

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