Comparison of FTDP-17 IVS10+16 patient derived hiPSC and ZFN engineered hiPSC

The development of an effective therapy against tauopathies like Alzheimer’s disease (AD) and frontotemporal dementia (FTD) remains challenging, partly due to limited access to fresh brain tissue, the lack of translational in vitro disease models and the fact that underlying molecular pathways remain to be deciphered. Several genes play an important role in the pathogenesis of AD and FTD, one of them being the MAPT gene encoding the microtubule-associated protein tau. Over the past few years, it has been shown that induced pluripotent stem cells (iPSC) can be used to model various human disorders and can serve as translational in vitro tools. Therefore, we generated iPSC harboring the pathogenic FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) associated mutations IVS10+16 with and without P301S in MAPT using Zinc Finger Nuclease technology. Whole transcriptome analysis of MAPT IVS10+16 neurons reveals neuronal subtype differences, reduced neural progenitor proliferation potential and aberrant WNT signaling. Notably, all phenotypes were recapitulated using patient-derived neurons. Finally, an additional P301S mutation causes an increased calcium bursting frequency, reduced lysosomal acidity and tau oligomerization. Altogether, these tau mutant iPSC lines allow us to study IVS10+16 and P301S mutations in an isogenic background and to unravel a potential link between pathogenic 4R tau expression and FTDP-17. This study includes 24 samples. There are 8 conditions considered, each with three biological replicates. Patient V97 (patient 1) and TSM (patient 2) have been described in more detail in PMID:26136155 and Verheyen et al., submitted Cells were lysed either at neural progenitor stage (NPC), which corresponds to DIV31 of hiPSC differentiation, or 5 weeks (W5) after plating of NPCs (DIV65 from hIPSC differentiation) and subjected to microarray Sigma CTR = control iPSC line provided by Sigma (iPSC0028) Sigma IVS10 = gene edited Sigma line with a MAPT mutation (IVS10+16) using Zinc Finger Nucleases (ZFN) Patient IVS10 V97 = patient 1 (PMID:26136155; Verheyen et al., submitted) Patient IVS10 TSM = patient 2 (PMID:26136155; Verheyen et al., submitted)