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Hum Mol Genet. 2015 Sep 15;24(18):5260-9. doi: 10.1093/hmg/ddv246. Epub 2015 Jul 1.

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.

Author information

1
Department of Molecular Neuroscience, UCL Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK.
2
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
3
Department of Clinical Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
4
Department of Molecular Neuroscience, UCL Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK, Division of Brain Sciences, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
5
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
6
Centre for Microsystems and Photonics, Electronic and Electrical Engineering, University of Strathclyde, Glasgow G1 1XW, UK.
7
MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK and.
8
Gurdon Institute, Cambridge Stem Cell Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
9
Department of Molecular Neuroscience, UCL Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK, selina.wray@ucl.ac.uk.

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.

PMID:
26136155
PMCID:
PMC4550814
DOI:
10.1093/hmg/ddv246
[Indexed for MEDLINE]
Free PMC Article

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