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Sci Rep. 2018 May 25;8(1):8097. doi: 10.1038/s41598-018-26397-2.

TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons.

Author information

1
Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland.
2
Ludwig-Maximilians University Munich, Feodor-Lynen-Strasse 17, 81377, München, Germany.
3
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058, Basel, Switzerland.
4
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield, S10 2HQ, UK.
5
Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.
6
MRC Centre for Regenerative Medicine, The University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
7
Harvard Stem Cell Institute, Harvard University, Howard Hughes Medical Institute, 7 Divinity Avenue, Cambridge, MA, 02138, USA.
8
ETH Zurich, Department of Biosystems Science and Engineering, Mattenstrasse 26, 4058, Basel, Switzerland.
9
Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland. verdon.taylor@unibas.ch.

Abstract

TAR DNA-binding protein 43 (TDP-43) is a key player in neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Accumulation of TDP-43 is associated with neuronal death in the brain. How increased and disease-causing mutant forms of TDP-43 induce cell death remains unclear. Here we addressed the role of TDP-43 during neural development and show that reduced TDP-43 causes defects in neural stem/progenitor cell proliferation but not cell death. However, overexpression of wild type and TDP-43A315T proteins induce p53-dependent apoptosis of neural stem/progenitors and human induced pluripotent cell (iPS)-derived immature cortical neurons. We show that TDP-43 induces expression of the proapoptotic BH3-only genes Bbc3 and Bax, and that p53 inhibition rescues TDP-43 induced cell death of embryonic mouse, and human cortical neurons, including those derived from TDP-43G298S ALS patient iPS cells. Hence, an increase in wild type and mutant TDP-43 induces p53-dependent cell death in neural progenitors developing neurons and this can be rescued. These findings may have important implications for accumulated or mutant TDP-43 induced neurodegenerative diseases.

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