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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.

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


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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