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. Issue 10 (20th July 2018)

• Record Type: Journal Article
• Authors: García‐León, Juan Antonio; Cabrera‐Socorro, Alfredo; Eggermont, Kristel; Swijsen, Ann; Terryn, Joke; Fazal, Raheem; Nami, FatemehArefeh; Ordovás, Laura; Quiles, Ana; Lluis, Frederic; Serneels, Lutgarde; Wierda, Keimpe; Sierksma, Annerieke; Kreir, Mohamed; Pestana, Francisco; Van Damme, Philip; De Strooper, Bart; Thorrez, Lieven; Ebneth, Andreas; Verfaillie, Catherine M.
• Is Part Of: Alzheimer's & dementia. Volume 14:Issue 10(2018)
• Page Start: 1261
• Page End: 1280
• Publication Date: 2018-07-20
• Subjects: Tauopathies -- Frontotemporal dementia -- Parkinsonism linked to chromosome 17 -- Progressive supranuclear palsy -- Alzheimer's disease -- CRISPR‐Cas -- Disease modeling -- Drug screening -- Neurodegeneration; Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1016/j.jalz.2018.05.007
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Introduction: 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. Methods: 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. Results: 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. Discussion: 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.