摘要Cytoplasmic accumulation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis(ALS)and other neurodegenerative diseases.While current studies have primarily focused on gene regulation mediated by full-length nuclear TDP-43,the potential effects of cytoplasmic TDP-43 fragments remain less explored.Our previous findings demonstrated that primate-specific cleavage of TDP-43 contributes to its cytoplasmic localization,prompting further investigation into its pathological effects.In the cynomolgus monkey brain,we observed that mutant or truncated TDP-43 was transported onto the ribosome organelle.Ribosome-associated transcriptomic analysis revealed dysregulation of apoptosis-and lysosome-related genes,indicating that cytoplasmic TDP-43 induces neurotoxicity by binding to ribosomes and disrupting mRNA expression.These findings provide mechanistic insights into the gain-of-function effects of pathological TDP-43.