Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes

• Published in: Stem cell reports Vol. 11; no. 2; pp. 363 - 379
• Main Authors: Verheyen, An, Diels, Annick, Reumers, Joke, Van Hoorde, Kirsten, Van den Wyngaert, Ilse, van Outryve d’Ydewalle, Constantin, De Bondt, An, Kuijlaars, Jacobine, De Muynck, Louis, De Hoogt, Ronald, Bretteville, Alexis, Jaensch, Steffen, Buist, Arjan, Cabrera-Socorro, Alfredo, Wray, Selina, Ebneth, Andreas, Roevens, Peter, Royaux, Ines, Peeters, Pieter J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-08-2018; Elsevier
• Subjects: disease modelling; FTDP-17; iPSC; MAPT; ZFN; ZFN; MAPT; disease modelling; FTDP-17; iPSC
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.06.022

Tauopathies such as frontotemporal dementia (FTD) remain incurable to date, partially due to the lack of translational in vitro disease models. The MAPT gene, encoding the microtubule-associated protein tau, has been shown to play an important role in FTD pathogenesis. Therefore, we used zinc finger nucleases to introduce two MAPT mutations into healthy donor induced pluripotent stem cells (iPSCs). The IVS10+16 mutation increases the expression of 4R tau, while the P301S mutation is pro-aggregant. Whole-transcriptome analysis of MAPT IVS10+16 neurons reveals neuronal subtype differences, reduced neural progenitor proliferation potential, and aberrant WNT/SHH signaling. Notably, these neurodevelopmental phenotypes could be recapitulated in neurons from patients carrying the MAPT IVS10+16 mutation. Moreover, the additional pro-aggregant P301S mutation revealed additional phenotypes, such as an increased calcium burst frequency, reduced lysosomal acidity, tau oligomerization, and neurodegeneration. This series of iPSCs could serve as a platform to unravel a potential link between pathogenic 4R tau and FTD.
•Analysis of ZFN-engineered MAPT IVS10+16 with or without additional P301S mutation•Neurodevelopmental phenotypes in ZFN and patient-derived MAPT IVS10+16 neurons•Neurodegenerative phenotypes in MAPT IVS10+16/P301S double-mutant neurons
In this article, Verheyen and colleagues introduced 2 MAPT mutations (IVS10+16/P301S) into healthy donor iPSCs. Characterization of MAPT IVS10+16 neurons revealed neurodevelopmental neuron subtype differences, reduced neural progenitor proliferation, and aberrant WNT/SHH signaling, while the additional pro-aggregant P301S mutation revealed phenotypes more related to neurodegeneration. These iPSCs could help to unravel a potential link between pathogenic 4R tau and FTD.