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Title: | Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes | Authors: | Verheyen, An Diels, Annick Reumers, Joke Van Hoorde, Kirsten Van den Wyngaert, Ilse d'Ydewalle, Constantin van Outryve 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. |
Issue Date: | 2018 | Publisher: | CELL PRESS | Source: | STEM CELL REPORTS, 11(2), p. 363-379 | Abstract: | 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. | Notes: | [Verheyen, An; Diels, Annick; Reumers, Joke; Van den Wyngaert, Ilse; d'Ydewalle, Constantin van Outryve; De Bondt, An; De Muynck, Louis; De Hoogt, Ronald; Bretteville, Alexis; Jaensch, Steffen; Buist, Arjan; Cabrera-Socorro, Alfredo; Ebneth, Andreas; Roevens, Peter; Royaux, Ines; Peeters, Pieter J.] Janssen Res & Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium. [Van Hoorde, Kirsten] Open Analyt NV, B-2600 Antwerp, Belgium. [Kuijlaars, Jacobine] Hasselt Univ, Biomed Res Inst, B-3590 Diepenbeek, Belgium. [Wray, Selina] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 1PJ, England. | Document URI: | http://hdl.handle.net/1942/28504 | ISSN: | 2213-6711 | e-ISSN: | 2213-6711 | DOI: | 10.1016/j.stemcr.2018.06.022 | ISI #: | 000441583100007 | Rights: | 2018 The Author(s).This is an open access article under the CC BY license | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2019 |
Appears in Collections: | Research publications |
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verheyen 1.pdf | Published version | 7.04 MB | Adobe PDF | View/Open |
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