| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2016 |
| Předmět: |
|
| Zdroj: |
Stem Cell Reports, Vol 7, Iss 3, Pp 325-340 (2016) |
| Druh dokumentu: |
article |
| ISSN: |
2213-6711 |
| DOI: |
10.1016/j.stemcr.2016.08.001 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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