García-León, JA;
Cabrera-Socorro, A;
Eggermont, K;
Swijsen, A;
Terryn, J;
Fazal, R;
Nami, F;
... Verfaillie, CM; + view all
(2018)
Generation of a human induced pluripotent stem cell-based model for tauopathies combining three microtubule-associated protein tau mutations which displays several phenotypes linked to neurodegeneration.
Alzheimer's & Dementia
, 14
(10)
pp. 1261-1280.
10.1016/j.jalz.2018.05.007.
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Abstract
Tauopathies are neurodegenerative diseases characterized by TAU protein-related pathology, including frontotemporal dementia and Alzheimer's disease among others. Mutant TAU animal models are available, but none of them faithfully recapitulates human pathology and are not suitable for drug screening. To create a new in vitro tauopathy model, we generated a footprint-free triple MAPT-mutant human induced pluripotent stem cell line (N279K, P301L, and E10+16 mutations) using clustered regularly interspaced short palindromic repeats-FokI and piggyBac transposase technology. Mutant neurons expressed pathogenic 4R and phosphorylated TAU, endogenously triggered TAU aggregation, and had increased electrophysiological activity. TAU-mutant cells presented deficiencies in neurite outgrowth, aberrant sequence of differentiation to cortical neurons, and a significant activation of stress response pathways. RNA sequencing confirmed stress activation, demonstrated a shift toward GABAergic identity, and an upregulation of neurodegenerative pathways. In summary, we generated a novel in vitro human induced pluripotent stem cell TAU-mutant model displaying neurodegenerative disease phenotypes that could be used for disease modeling and drug screening.
| Type: | Article |
|---|---|
| Title: | Generation of a human induced pluripotent stem cell-based model for tauopathies combining three microtubule-associated protein tau mutations which displays several phenotypes linked to neurodegeneration |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jalz.2018.05.007 |
| Publisher version: | https://doi.org/10.1016/j.jalz.2018.05.007 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Alzheimer's disease, CRISPR-Cas, Disease modeling, Drug screening, Frontotemporal dementia, Neurodegeneration, Parkinsonism linked to chromosome 17, Progressive supranuclear palsy, Tauopathies |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10055424 |
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