ArticleHuman molecular genetics2015
Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers.
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99 citing papers in PubMed, 154 citations in OpenAlex.
- Article
- Review
- NAT10 inhibition corrects nuclear defects in tau mutant human neurons and extends lifespan in aiScience · 2026Article
- Human Stem Cell-Derived Models of the Alzheimer's Disease Neuroimmune System.International journal of molecular sciences · 2026Review
- Scalable human neuronal models of tauopathy producing endogenous seed-competent 4R tau.Science advances · 2026Article
- Integrative genomic and functional analyses reveal NINL as a modulator of tau aggregation.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Oxidized MIF is an Alzheimer's disease drug target relaying external risk factors to tau pathology.Cell reports. Medicine · 2026Article
- Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer's patient-derived cortical neurons.Molecular psychiatry · 2026Article
- Integrative Genomic and Functional Analyses Reveal NINL as a Modulator of Tau Aggregation.bioRxiv : the preprint server for biology · 2025Article
- Genetics of Frontotemporal Dementia in the Serbian Population: Findings from a Hospital-Based Cohort.Neurology international · 2025Article
- Mutant MAPT Induces rDNA Transcriptional Hyperactivation and Nucleolar Stress in Cellular Models.Research square · 2025Article
- A phenotypic screen for novel small molecules that correct tau-mediated pathologies in human frontotemporal dementia neurons.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Generation of human induced pluripotent stem cell-derived cortical neurons expressing the six tau isoforms.Journal of Alzheimer's disease : JAD · 2025Article
- Stable isotope labelling kinetics of neurofilament light.Brain communications · 2025Article
- Development of MAPT S305 mutation human iPSC lines exhibiting elevated 4R tau expression and functional alterations in neurons and astrocytes.Cell reports · 2024Article
- Microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia.Acta neuropathologica · 2024Article
- A framework for translating tauopathy therapeutics: Drug discovery to clinical trials.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Review
- Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis.Brain : a journal of neurology · 2024Review
- The annotation ofScience advances · 2024Article
- Lineage-specific splicing regulation of MAPT gene in the primate brain.Cell genomics · 2024Article
39 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 6 institutions in 1 country.
Funding
Abstract
The alternative splicing of the tau gene, MAPT, generates six protein isoforms in the adult human central nervous system (CNS). Tau splicing is developmentally regulated and dysregulated in disease. Mutations in MAPT that alter tau splicing cause frontotemporal dementia (FTD) with tau pathology, providing evidence for a causal link between altered tau splicing and disease. The use of induced pluripotent stem cell (iPSC)-derived neurons has revolutionized the way we model neurological disease in vitro. However, as most tau mutations are located within or around the alternatively spliced exon 10, it is important that iPSC-neurons splice tau appropriately in order to be used as disease models. To address this issue, we analyzed the expression and splicing of tau in iPSC-derived cortical neurons from control patients and FTD patients with the 10 + 16 intronic mutation in MAPT. We show that control neurons only express the fetal tau isoform (0N3R), even at extended time points of 100 days in vitro. Neurons from FTD patients with the 10 + 16 mutation in MAPT express both 0N3R and 0N4R tau isoforms, demonstrating that this mutation overrides the developmental regulation of exon 10 inclusion in our in vitro model. Further, at extended time points of 365 days in vitro, we observe a switch in tau splicing to include six tau isoforms as seen in the adult human CNS. Our results demonstrate the importance of neuronal maturity for use in in vitro modeling and provide a system that will be important for understanding the functional consequences of altered tau splicing.
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