Fig. 3

Models of TDP-43 toxicity. A Under normal conditions, TDP-43 expression is under strict regulation and is predominantly located in the nucleus. B When subjected to stress, such as DNA damage, the TDP-43 protein moves from the nucleus to cytoplasm, where it forms phosphorylated pre-inclusion bodies. C This leads to the loss of normal nuclear TDP-43. If TDP-43 autoregulation occurs within the nucleus, loss of TDP-43 stimulates the cell to produce more TDP-43 protein, thereby aggravating the accumulation of TDP-43 in the cytoplasm. D If TDP-43 autoregulation occurs within the cytoplasm, the increase in cytoplasmic TDP-43 can result in an increase in TDP-43 autoregulation and a decrease in the synthesis of new TDP-43 protein. E Regardless of whether TDP-43 autoregulation occurs in the nucleus or cytoplasm, it ultimately leads to neuronal death