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.
在肌萎缩侧索硬化症（ALS）等多种神经退行疾病中，TDP-43蛋白常被发现在神经细胞的胞质中异常积累。目前很多研究集中在全长型TDP-43在细胞核内对基因编辑的作用，而相对较少关注片段型TDP-43在细胞质中的影响。之前报道灵长类特异性切割TDP-43可导致其截短产物定位于细胞质中，对研究病理性TDP-43的潜在毒性提供了便利。在食蟹猴脑中，我们发现突变的片段型TDP-43可定位于核糖体细胞器；并通过核糖体联用转录组学分析，鉴定了一些凋亡相关和溶酶体相关的失调基因。表明灵长类脑中胞质TDP-43仍可通过与核糖体结合并改变多种mRNA表达，从而引发神经细胞毒性。上述发现为了解病理性TDP-43的功能获得机制提供了更多思路。.
Keywords: Gain-of-function; Non-human primates; Ribosomes; TDP-43.