Vogt, Miriam A.Ehsaei, ZahraKnuckles, PhilipHigginbottom, AdrianHelmbrecht, Michaela S.Kunath, TiloEggan, KevinWilliams, LuisShaw, Pamela J.Wurst, WolfgangFloss, ThomasHuber, Andrea B.Taylor, Verdon2018-06-272018Vogt, M. A., Z. Ehsaei, P. Knuckles, A. Higginbottom, M. S. Helmbrecht, T. Kunath, K. Eggan, et al. 2018. “TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons.” Scientific Reports 8 (1): 8097. doi:10.1038/s41598-018-26397-2. http://dx.doi.org/10.1038/s41598-018-26397-2.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160371TAR 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.en-USJournal Article2018-06-2710.1038/s41598-018-26397-2