Figure 4.

Transactive response DNA-binding protein (TDP-43 or TARDBP) may bind to single-stranded retrotransposons or to retrotransposons embedded in pre-mRNA and may regulate TE abundance or affect A-to-I editing. Normally, TDP-43 is proposed to act as a scavenger of TE-derived transcripts and regulates TE abundance. When TDP-43 function becomes comprised, as in certain neurodegenerative diseases with depletion of TDP-43 from the nucleus and aggreation in the neuronal cytoplasm, TEs become overexpressed (shown left-hand; Krug et al., 2017). Depicted right-hand, TDP-43 can also bind to retrotransposons contained in pre-mRNA and it was proposed that TDP-43 limits the extent of ADAR-mediated A-to-I editing in intronic inverted repeat dsRNA structures. A-to-I editing increases if nuclear TDP-43 is depleted. The bidirectional arrow questions whether the interaction is reciprocal and whether altered A-to-I editing may also lead to compromised binding of TDP-43 to pre-mRNA with loss of nuclear TDP-43 predominance, translocation to the cytoplasm, and aggregation. Yellow parts represent exons (e).