RTP801/REDD1 is a stress-responsive protein overexpressed in neurodegenerative diseases such as Alzheimer’s disease (AD) that contributes to cognitive deficits and neuroinflammation. Here, we found that RTP801 interacts with HSPC117, DDX1 and CGI-99, three members of the tRNA ligase complex (tRNA-LC), which ligates the excised exons of intron-containing tRNAs and the mRNA exons of the transcription factor XBP1 during the unfolded protein response (UPR). We also found that RTP801 modulates the mRNA ligase activity of the complex in vitro since RTP801 knockdown promoted XBP1 splicing and the expression of its transcriptional target, SEC24D. Conversely, RTP801 overexpression inhibited the splicing of XBP1. Similarly, in human AD postmortem hippocampal samples, where RTP801 is upregulated, we found that XBP1 splicing was dramatically decreased. In the 5xFAD mouse model of AD, silencing RTP801 expression in hippocampal neurons promoted Xbp1 splicing and prevented the accumulation of intron-containing pre-tRNAs. Finally, the tRNA-enriched fraction obtained from 5xFAD mice promoted abnormal dendritic arborization in cultured hippocampal neurons, and RTP801 silencing in the source neurons prevented this phenotype. Altogether, these results show that elevated RTP801 impairs RNA processing in vitro and in vivo in the context of AD and suggest that RTP801 inhibition could be a promising therapeutic approach.

中文翻译：

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RTP801 在阿尔茨海默病中与 tRNA 连接酶复合物相互作用并失调其 RNA 连接酶活性


RTP801/REDD1 是一种应激反应蛋白，在阿尔茨海默病 （AD） 等神经退行性疾病中过表达，可导致认知缺陷和神经炎症。在这里，我们发现 RTP801 与 HSPC117、DDX1 和 CGI-99 相互作用，这是 tRNA 连接酶复合物 （tRNA-LC） 的三个成员，它在未折叠蛋白反应 （UPR） 期间连接含内含子的 tRNA 的切除外显子和转录因子 XBP1 的 mRNA 外显子。我们还发现 RTP801 在体外调节复合物的 mRNA 连接酶活性，因为 RTP801 敲除促进了 XBP1 剪接及其转录靶标 SEC24D 的表达。相反，RTP801 过表达抑制了 XBP1 的剪接。同样，在 RTP801 上调的人类 AD 死后海马样本中，我们发现 XBP1 剪接显着减少。在 AD 的 5xFAD 小鼠模型中，沉默海马神经元中 RTP801 的表达促进了 Xbp1 剪接并阻止了含有内含子的前 tRNA 的积累。最后，从 5xFAD 小鼠获得的富含 tRNA 的部分促进了培养的海马神经元中异常的树突状树枝化，而源神经元中的 RTP801 沉默阻止了这种表型。总而言之，这些结果表明，在 AD 的情况下，升高的 RTP801 会损害体外和体内的 RNA 加工，并表明 RTP801 抑制可能是一种很有前途的治疗方法。