eprintid: 10080365 rev_number: 24 eprint_status: archive userid: 608 dir: disk0/10/08/03/65 datestamp: 2019-08-22 14:49:46 lastmod: 2021-09-30 22:46:41 status_changed: 2019-08-22 14:49:46 type: article metadata_visibility: show creators_name: Verheyen, A creators_name: Diels, A creators_name: Reumers, J creators_name: Van Hoorde, K creators_name: Van den Wyngaert, I creators_name: d'Ydewalle, CVO creators_name: De Bondt, A creators_name: Kuijlaars, J creators_name: De Muynck, L creators_name: De Hoogt, R creators_name: Bretteville, A creators_name: Jaensch, S creators_name: Buist, A creators_name: Cabrera-Socorro, A creators_name: Wray, S creators_name: Ebneth, A creators_name: Roevens, P creators_name: Royaux, I creators_name: Peeters, PJ title: Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 keywords: FTDP-17, MAPT, iPSC, ZFN, disease modelling note: © 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 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. date: 2018-08-14 date_type: published publisher: CELL PRESS official_url: https://doi.org/10.1016/j.stemcr.2018.06.022 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Journal Article verified: verified_manual elements_id: 1575903 doi: 10.1016/j.stemcr.2018.06.022 language_elements: English lyricists_name: Wray, Selina lyricists_id: SWRAY93 actors_name: Kalinowski, Damian actors_id: DKALI47 actors_role: owner full_text_status: public publication: Stem Cell Reports volume: 11 number: 2 pagerange: 363-379 pages: 17 issn: 2213-6711 citation: Verheyen, A; Diels, A; Reumers, J; Van Hoorde, K; Van den Wyngaert, I; d'Ydewalle, CVO; De Bondt, A; ... Peeters, PJ; + view all <#> Verheyen, A; Diels, A; Reumers, J; Van Hoorde, K; Van den Wyngaert, I; d'Ydewalle, CVO; De Bondt, A; Kuijlaars, J; De Muynck, L; De Hoogt, R; Bretteville, A; Jaensch, S; Buist, A; Cabrera-Socorro, A; Wray, S; Ebneth, A; Roevens, P; Royaux, I; Peeters, PJ; - view fewer <#> (2018) Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes. Stem Cell Reports , 11 (2) pp. 363-379. 10.1016/j.stemcr.2018.06.022 <https://doi.org/10.1016/j.stemcr.2018.06.022>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10080365/1/Wray_Genetically%20Engineered%20iPSC-Derived%20FTDP-17%20MAPT%20Neurons%20Display%20Mutation-Specific%20Neurodegenerative%20and%20Neurodevelopmental%20Phenotypes_VoR.pdf document_url: https://discovery.ucl.ac.uk/id/eprint/10080365/7/Wray_Correction.%20Genetically%20Engineered%20iPSC-Derived%20FTDP-17%20MAPT_VoR.pdf