Mis-spliced transcripts generate <i>de novo</i> proteins in TDP-43-related ALS/FTD.

ABSTRACT: Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to ALS and FTD, leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. However, the possibility of de novo protein synthesis from cryptic exon transcripts has not been explored. Here, we show that mRNA transcripts harboring cryptic exons generate de novo proteins both in TDP-43 deficient cellular models and in disease. Using coordinated transcriptomic and proteomic studies of TDP-43 depleted iPSC-derived neurons, we identified numerous peptides that mapped to cryptic exons. Cryptic exons identified in iPSC models were highly pr

SUBMITTER: Seddighi S 

PROVIDER: S-EPMC9900763 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature