1. Ribosome-associated pathological TDP-43 alters the expression of multiple mRNAs in the monkey brain.
- Author
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Deng FY, Zhu GL, Ou KL, Zhu LH, Jia QQ, Wang X, Guo MW, Li B, Li SH, Li XJ, and Yin P
- Subjects
- Animals, Gene Expression Regulation, RNA, Messenger metabolism, RNA, Messenger genetics, Brain metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Ribosomes metabolism, Ribosomes genetics, Macaca fascicularis genetics
- Abstract
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.
- Published
- 2025
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