UMMS Affiliation

Department of Neurology

Date

9-13-2016

Document Type

Article

Disciplines

Cell Biology | Nervous System Diseases | Neurology | Neuroscience and Neurobiology

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.

Rights and Permissions

Citation: Stem Cell Reports. 2016 Sep 13;7(3):325-40. doi: 10.1016/j.stemcr.2016.08.001. Epub 2016 Sep 1. Link to article on publisher's site

DOI of Published Version

10.1016/j.stemcr.2016.08.001

Comments

Full author list omitted for brevity. For full list of authors see article.

Related Resources

Link to Article in PubMed

Journal Title

Stem cell reports

PubMed ID

27594585

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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