Deng Fu-Yu, Zhu Gao-Lu, Ou Kai-Li, Zhu Long-Hong, Jia Qing-Qing, Wang Xiang, Guo Ming-Wei, Li Bang, Li Shi-Hua, Li Xiao-Jiang, Yin Peng
Guangdong Key Laboratory of Non-human Primate Research, Ministry of Education Key Laboratory of CNS Regeneration, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong 510632, China.
Shenzhen Institute for Drug Control, Shenzhen Testing Center of Medical Devices, In vitro Diagnostic Reagents Testing Department, Shenzhen, Guangdong 518057, China.
Zool Res. 2025 Mar 18;46(2):263-276. doi: 10.24272/j.issn.2095-8137.2024.286.
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.
TDP-43的细胞质积聚是肌萎缩侧索硬化症（ALS）和其他神经退行性疾病的病理标志。虽然目前的研究主要集中在全长核TDP-43介导的基因调控上，但细胞质TDP-43片段的潜在影响仍较少被探索。我们之前的研究结果表明，TDP-43的灵长类特异性切割有助于其细胞质定位，促使我们进一步研究其病理作用。在食蟹猴大脑中，我们观察到突变或截短的TDP-43被转运到核糖体细胞器上。核糖体相关转录组分析揭示了凋亡和溶酶体相关基因的失调，表明细胞质TDP-43通过与核糖体结合并破坏mRNA表达来诱导神经毒性。这些发现为病理性TDP-43的功能获得效应提供了机制性见解。
