RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress Response
Figure 1
Loss of function of TDP-1 extends the lifespan and reduces protein aggregation in C. elegans in a DAF-16-dependent manner.
(A) Survival curves of wild-type (black) and tdp-1(ok803lf) loss-of-function mutant (red) demonstrate a significant lifespan extension. n>100, p<0.001 The lifespan-extending effect of tdp-1(ok803lf) is blocked by a loss of function of DAF-16 in daf-16(mu86lf), as shown by the survival curves (green and blue). n>100, p<0.001. (B) Survival curves of daf-2(e1370lf) loss-of-function mutant alone (black) and the daf-2(e1370lf);tdp-1(ok803lf) double mutant (blue) show a further lifespan extension with the loss of TDP-1. n>100, p<0.001. (C) Schematic diagram of the genetic pathway for TDP-1 regulation of the lifespan in relation to the DAF-2–DAF-16 pathway. (D) Loss of daf-16 abolished the reduction of protein aggregation conferred by loss of function of TDP-1. Transgenic TDP-C25-YFP expressed in C. elegans neurons was fractionated in to soluble supernatant and insoluble pellet before western blot analysis using a YFP antibody. The effects of single mutant tdp-1(ok803lf) and double mutant tdp-1(ok803lf); daf-16(mu86lf) were compared. (E) Quantitative measurement of mRNA levels of select DAF-16 targets genes in wild-type and tdp-1(ok803lf) C. elegans. n>6, *p<0.001; error bars represent SEM.