Figures & data
Figure 1. RNA lariats decoy cytoplasmic TDP-43 aggregates. (A) When introns are spliced out of pre-mRNAs, Dbr1 debranches the excised lariat introns and then they are degraded by cellular exonucleases. In the absence of Dbr1 activity, intronic lariats accumulate in the cytoplasm. (B) A hypothetical model of how Dbr1 inhibitors could be pursued as a therapeutic strategy for ALS. In a healthy motor neuron, TDP-43 is localized to the nucleus. In ALS, TDP-43 is lost from the nucleus and accumulates in the cytoplasm where it forms large aggregates. These aggregates might bind and inhibit essential cellular RNAs and RNA-binding proteins. Inhibiting Dbr1 would lead to the accumulation of RNA lariats in the cytoplasm and these might act as decoys for TDP-43, relieving the inhibition of the essential RNAs and RNA-binding proteins.
Figure 2. TDP-43 in ALS: Gain or loss-of-function? Spinal cord sections from an unaffected individual (A) or from an ALS patient (B) immunostained for TDP-43. (A) In the unaffected individual, TDP-43 is localized to the nucleus of motor neurons (arrows). (B) In motor neurons of ALS patients TDP-43 is depleted from the nucleus (arrow) and accumulates in the cytoplasm in large aggregates (*).
