RT Journal Article
T1 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.
A1 García-León, Juan Antonio
A1 Cabrera-Socorro, Alfredo
A1 Eggermont, Kristel
A1 Swijsen, Ann
A1 Terryn, Joke
A1 Fazal, Raheem
A1 Nami, FatemehArefeh
A1 Ordovás, Laura
A1 Quiles, Ana
A1 Lluis, Frederic
A1 Serneels, Lutgarde
A1 Wierda, Keimpe
A1 Sierksma, Annerieke
A1 Kreir, Mohamed
A1 Pestana, Francisco
A1 Van Damme, Philip
A1 De Strooper, Bart
A1 Thorrez, Lieven
A1 Ebneth, Andreas
A1 Verfaillie, Catherine M
K1 Alzheimer's disease
K1 CRISPR-Cas
K1 Disease modeling
K1 Drug screening
K1 Frontotemporal dementia
K1 Neurodegeneration
K1 Parkinsonism linked to chromosome 17
K1 Progressive supranuclear palsy
K1 Tauopathies
AB 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.
YR 2018
FD 2018-07-20
LK http://hdl.handle.net/10668/12743
UL http://hdl.handle.net/10668/12743
LA en
DS RISalud
RD Apr 19, 2025