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.

García-León, Juan AntonioCabrera-Socorro, AlfredoEggermont, KristelSwijsen, AnnTerryn, JokeFazal, RaheemNami, FatemehArefehOrdovás, LauraQuiles, AnaLluis, FredericSerneels, LutgardeWierda, KeimpeSierksma, AnneriekeKreir, MohamedPestana, FranciscoVan Damme, PhilipDe Strooper, BartThorrez, LievenEbneth, AndreasVerfaillie, Catherine M2023-01-252023-01-252018-07-20http://hdl.handle.net/10668/12743Tauopathies 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.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Alzheimer's diseaseCRISPR-CasDisease modelingDrug screeningFrontotemporal dementiaNeurodegenerationParkinsonism linked to chromosome 17Progressive supranuclear palsyTauopathiesCRISPR-Cas SystemsCell LineHumansInduced Pluripotent Stem CellsMembrane PotentialsMutationNerve DegenerationNeurogenesisNeuronal OutgrowthNeuronsPhenotypeTauopathiesTranscriptometau ProteinsGeneration 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.research article30036493open access10.1016/j.jalz.2018.05.0071552-5279https://doi.org/10.1016/j.jalz.2018.05.007