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

An Verheyen,Pieter J Peeters,Annick Diels,Ines Royaux,Ilse Van Den Wyngaert,An De Bondt,Kirsten Van Hoorde,Andreas Ebneth,Arjan Buist,Jacobine Kuijlaars,Alexis Bretteville,Alfredo Cabrera-Socorro,Selina Wray,Louis De Muynck,Peter Roevens,Constantin Van Outryve D’Ydewalle,Steffen Jaensch,Joke Reumers,Ronald De Hoogt

doi:10.1016/j.stemcr.2018.06.022

An Verheyen, Pieter J Peeters + Show 17 more

Open Access

https://doi.org/10.1016/j.stemcr.2018.06.022

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Abstract

SummaryTauopathies 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.

Highlights

Tauopathies including frontotemporal dementia (FTD) and Alzheimer disease (AD), are a group of neurodegenerative diseases characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau in the human brain (Spillantini and Goedert, 2013)
Neurons of Patients with the IVS10+16 Mutation Display a Similar Phenotype as zinc finger nuclease (ZFN)-Gene-Edited IVS10+16 Neurons As we were unable to link our observed phenotypes to 4R tau expression only, we evaluated whether these phenotypes could be confirmed in FTDP-17 patient-derived cells with the same IVS10+16 mutation
Regarding FTD-related genes, we found a significant increase in TARDBP (TDP-43) at DIV65, while GRN was significantly lower at the NPC stage in all MAPT IVS10+16 cells (Table S4)

Summary

Introduction

Tauopathies including frontotemporal dementia (FTD) and Alzheimer disease (AD), are a group of neurodegenerative diseases characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau in the human brain (Spillantini and Goedert, 2013). Under pathological conditions, several MAPT gene mutations have been linked to hyperphosphorylation and aggregation of tau into neurofibrillary tangles (NFTs) resulting in FTD (Hutton et al, 1998). Alternative splicing of exon 2, 3, and 10 of the MAPT gene on chromosome 17 leads to the expression of six different tau isoforms in the adult human brain, with the longest isoform (2N4R) harboring two N-terminal insertions (exon 2 and 3) and the inclusion of a fourth repeat (exon 10) in tau’s microtubule binding domain. The function and neuronal expression pattern of these different tau isoforms remain to be elucidated, correct splicing seems to be necessary to keep neurons functional, as unbalanced 4R:3R tau ratios are linked with neurodegenerative disorders such as FTD and Huntington disease (Hutton et al, 1998; FernandezNogales et al, 2014, 2016). MAPT mutations that promote the inclusion of exon 10 appear to be sufficient to trigger disease (Hutton et al, 1998)

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