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Vogt, M.A.* ; Ehsaei, Z.* ; Knuckles, P.* ; Higginbottom, A.* ; Helmbrecht, M.S. ; Kunath, T.* ; Eggan, K.* ; Williams, L.A.* ; Shaw, P.J.* ; Wurst, W. ; Floss, T. ; Huber, A.B. ; Taylor, V.*

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

Sci. Rep. 8:8097 (2018)

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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-43A315Tproteins 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-43G298SALS 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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