Ribosome associated pathological TDP-43 alters multiple mRNAs expression in the monkey brain

The cytoplasmic accumulation of TDP-43 is the pathological hallmark in Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases. Current studies mainly focus on the gene editing by full-length TDP-43 in the nucleus, but there has been relatively less investigation into the potential effects of cytoplasmic cleaved TDP-43 fragments. We previously reported that the primate-specific cleavage of TDP-43 accounts for the cytoplasmic localization of truncated TDP-43, which prompted us to study the potential toxic effects of pathological TDP-43. In the Cynomolgus monkey brain, we found that the mutant or truncated TDP-43 was transported onto the ribosome organelle. Through ribosome-associated transcriptomics analysis, we identified the dysregulation of some apoptosis- and lysosome-related genes. These findings suggest that the cytoplasmic TDP-43 in the primate brain cause neurotoxicity by binding to ribosomes and altering the expression of multiple mRNAs. These findings provide additional insights into the mechanisms underlying the gain of function of pathological TDP-43.