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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

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Sposito, Teresa, Preza, Elisavet, Mahoney, Colin J., Setó-Salvia, Núria, Ryan, Natalie S., Morris, Huw R., Arber, Charles, Devine, Michael J. +10 more·2015·Human Molecular Genetics
DOI 10.1093/hmg/ddv246PMC PMC4550814
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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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  • iPSC-derived neurons or NGN2-induced neurons have been unable to produce the 4R Tau isoform found in adult human brains; only the fetal 0N3R splicing isoform is produced, even after one year of differentiation.

    “One of the significant hurdles in modeling AD with iPSC-derived neurons or NGN2-induced neurons for the past decade has been their inability to produce the 4R Tau isoform found in adult human brains [19–22]; only the fetal 0N3R splicing isoform is produced, even after one year of differentiation [19].”

    From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [19]

    The Results section (‘Postnatal tau splicing is observed at extended time points in vitro’) supports fetal 0N3R-only expression through 100 days, but directly contradicts the claim that it persists after one year: control iPSC-derived neurons expressed 4R tau at day 365. The paper does not report results for NGN2-induced neurons. (LLM, conf=0.90)

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  • Little 4R tau is expressed in iPSC-derived models without a splice-site mutation.

    “This is important because little 4R tau is expressed in induced pluripotent stem cell (iPSC)-derived models without a splice-site mutation (lovino et al., 2015; Sato et al., 2018; Sposito et al., 2015; Verheyen et al., 2018).”

    From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Sposito et al., 2015

    The Results section reports no detectable 4R tau mRNA in control iPSC-derived cortical neurons through 100 days of differentiation, supporting the claim for those cultures. But the Results section on extended culture reports robust 4R expression in control neurons at 365 days, so the unqualified statement does not hold across all culture durations. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • iPSC-derived neurons at DIV 7-8 predominantly express 3R tau, with 4R tau expression increasing during maturation.

    “iPSC-derived neurons at DIV 7–8 predominantly express 3R tau, with 4R tau expression increasing during maturation”

    From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Sposito et al., 2015

    The Results sections on tau expression and postnatal splicing (page unavailable) report only 3R tau in control iPSC-derived neurons through Day 100, followed by both 3R and 4R tau at Day 365. They do not report tau isoforms at DIV 7–8; the earliest reported detection is tau mRNA at Day 20 and protein at Day 30. Thus, the maturation pattern is supported, but the specific DIV 7–8 claim is not. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • DIV7-8 iPSC-derived neurons predominantly express 3R tau, whereas our rescue experiments used 4R0N tau.

    “DIV7–8 iPSC-derived neurons predominantly express 3R tau (Iovino et al., 2010; Iovino et al., 2015; Sposito et al., 2015), whereas our rescue experiments used 4R0N tau”

    From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Sposito et al., 2015

    The Results section reports that control iPSC-derived cortical neurons expressed 3R tau from Day 20 through Day 100 of differentiation, supporting the predominant-3R point. It does not establish tau expression at DIV7–8. The statement about the citing authors’ rescue experiments is not attributed to this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Sposito, T., Preza, E., Mahoney, C. J., Setó-Salvia, N., Ryan, N. S., Morris, H. R., Arber, C., Devine, M. J., Houlden, H., Warner, T. T., Bushell, T. J., Zagnoni, M., Kunath, T., Livesey, F. J., Fox, N. C., Rossor, M. N., Hardy, J., & Wray, S.
Affiliations
  • UCL Queen Square Institute of Neurology (GB)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Hammersmith Hospital (GB)
  • University of Strathclyde (GB)
  • MRC Centre for Regenerative Medicine (GB)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
Corresponding author
Wray, Selina
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2015-07-01
Volume
24
Issue
18
Pages
5260-5269
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddv246
PMC
PMC4550814
OpenAlex
W2147718170
Cited by
148
References
4
Citations by year
2026: 9 · 2025: 13 · 2024: 15 · 2023: 8 · 2022: 12 · 2021: 23 · 2020: 11 · 2019: 13 · 2018: 13 · 2017: 13 · 2016: 12 · 2015: 6
FWCI
10.80
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Human Molecular Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion, other-oa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Eli Lilly and Janssen, Alzheimer's Research UK, CBD Solutions, UCB BioPharma
  • NIHR Queen Square Dementia Biomedical Research Unit
  • NIHR
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
MAPT, frontotemporal dementia, exon 10, alternative splicing, iPSC-derived neurons, cortical neurons, neuronal maturation, tau isoforms, disease modeling, in vitro disease model
MeSH terms
Cell Differentiation, Cell Line, Cerebral Cortex, Fibroblasts, Haplotypes, Humans, Infant, Infant, Newborn, Introns, Mutation, Neurons, Phosphorylation, Stem Cells, Biomarkers, tau Proteins, Alternative Splicing, RNA Splice Sites, Induced Pluripotent Stem Cells, Frontotemporal Dementia

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