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ZFN engineered hiPSC with the FTDP-17 associated MAPT IVS10+16 mutation w/wo additional P301S mutation

ABSTRACT: 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. Overall design: This study includes 48 samples. There are 16 treatments considered, each with at least three biological replicates. ZFN engineered (IVS10+16, monoallelic) and FTD patient-derived (IVS10+16, monoallelic) hiPSC have been differentiated into neurons using an established cortical differentiation protocol (PMID:22976355) with only minor modifications. 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) Time point represents weeks after plating of neural progenitors (NPCs); NPC = lysis 1 day after plating Wk3 = lysis 3 wks after plating NPCs = ± DIV51 from hiPSC differentiation Wk5 = lysis 5 wks after plating NPCs = ± DIV65 from hiPSC differentiation Wk7 = lysis 7 wks after plating NPCs = ± DIV80 from hiPSC differentiation

INSTRUMENT(S): [HG-U219] Affymetrix Human Genome U219 Array [CDF: Brainarray HGU219_Hs_ENTREZG_20.0.0]

ORGANISM(S): Homo Sapiens

SUBMITTER: An De Bondt  

PROVIDER: GSE104013 | GEO | 2018-08-01


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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-aggregan  ...[more]

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