TY  - JOUR
AV  - public
Y1  - 2018/08/14/
EP  - 379
TI  - Genetically Engineered iPSC-Derived FTDP-17 MAPT Neurons Display Mutation-Specific Neurodegenerative and Neurodevelopmental Phenotypes
KW  - FTDP-17
KW  -  MAPT
KW  -  iPSC
KW  -  ZFN
KW  -  disease modelling
PB  - CELL PRESS
N2  - 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.
ID  - discovery10080365
IS  - 2
N1  - © 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
VL  - 11
SP  - 363
A1  - Verheyen, A
A1  - Diels, A
A1  - Reumers, J
A1  - Van Hoorde, K
A1  - Van den Wyngaert, I
A1  - d'Ydewalle, CVO
A1  - De Bondt, A
A1  - Kuijlaars, J
A1  - De Muynck, L
A1  - De Hoogt, R
A1  - Bretteville, A
A1  - Jaensch, S
A1  - Buist, A
A1  - Cabrera-Socorro, A
A1  - Wray, S
A1  - Ebneth, A
A1  - Roevens, P
A1  - Royaux, I
A1  - Peeters, PJ
JF  - Stem Cell Reports
UR  - https://doi.org/10.1016/j.stemcr.2018.06.022
SN  - 2213-6711
ER  -