On 2015 Nov 24, Salzman Lab Journal Club commented:

This thought-provoking paper describes a potential mechanism for cryptic exon splicing due to TDP-43 proteinopathy. It is interesting to consider the evolutionary history of the sequence surrounding these cryptic exons and the origins of TDP-43 binding. The authors show that GU-repeats, the consensus motif for TDP-43, often flank these cryptically spliced exons. Is it that these GU repeats originally promoted the splicing of these cryptic exons and TDP-43 evolved the ability to bind GU repeats to restrict this process or did the GU-repeats arise later to repress the splicing by recruiting TDP-43, leading to repression? Additionally, we would be interested in seeing the effect of other engineered TDP-43 mutants and truncations on cryptically spliced exons, specifically, a mutant lacking the C-terminus and other splicing repressor domains and the full length TDP-43 rescue as simple controls.

On 2015 Nov 24, Salzman Lab Journal Club commented:

This thought-provoking paper describes a potential mechanism for cryptic exon splicing due to TDP-43 proteinopathy. It is interesting to consider the evolutionary history of the sequence surrounding these cryptic exons and the origins of TDP-43 binding. The authors show that GU-repeats, the consensus motif for TDP-43, often flank these cryptically spliced exons. Is it that these GU repeats originally promoted the splicing of these cryptic exons and TDP-43 evolved the ability to bind GU repeats to restrict this process or did the GU-repeats arise later to repress the splicing by recruiting TDP-43, leading to repression? Additionally, we would be interested in seeing the effect of other engineered TDP-43 mutants and truncations on cryptically spliced exons, specifically, a mutant lacking the C-terminus and other splicing repressor domains and the full length TDP-43 rescue as simple controls.