(CA)n oligonucleotides correct RNA mis-splicing in TDP-43 pathology (I)

The occurrence of extensive cryptic splicing following the depletion of nuclear TDP-43 results in impaired neuronal function and degeneration. Here, we show that oligonucleotides containing CA-repeat sequences can mimic TDP-43 pre-mRNA binding and broadly repress cryptic splicing events, reverse protein loss, and restore neuronal activity in TDP-43-depleted neurons. Our results indicate that (CA)n oligonucleotides are potential therapeutic agents to address global mis-splicing in TDP-43 proteinopathies. Overall design: Comparative alternative splicing analysis of RNA-seq data for hiPSC-derived glutamatergic neurons (FujiFilm Cellular Dynamics; Cat.R1034) after treatment with TDP43 antisense gapmers and (CA)n oligonucleotides.