Increased expression of fragmented tRNA promoted neuronal necrosis.
Increased expression of fragmented tRNA promoted neuronal necrosis.
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片段化 tRNA 表达增加促进神经元坏死
DOI：
10.1038/s41419-021-04108-6
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发表时间：
2021-08-30
影响因子：
9
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Cao Y;Liu K;Xiong Y;Zhao C;Liu L
众所周知，由过量谷氨酸释放诱导的神经元坏死会导致缺血性中风的发病和死亡。在过去几十年中，针对谷氨酸受体的策略并未取得理想的临床效果。寻找谷氨酸受体激活的下游机制可能为抑制细胞死亡提供新的靶点。先前我们的研究表明，H3K4三甲基化（H3K4me3）的增加在神经元坏死中起关键的有害作用；然而，这种组蛋白修饰的机制尚不清楚。通过全基因组小RNA测序，我们发现几种tRNA衍生片段（tRFs）和piwi相互作用RNA（piRNAs）在大鼠原代神经元培养物中谷氨酸诱导的神经元坏死中富集，并且这种富集依赖于H3K4me3的增加。令人惊讶的是，当我们将几种合成的tRFs和piRNA转染到神经元中时，tRFs而非piRNAs诱导了神经元肿胀和死亡。细胞死亡形态重现了谷氨酸诱导的神经元坏死。对于tRFs的细胞毒性作用，我们的数据表明蛋白质合成可能通过诱导核糖体停滞而受到抑制。通过对tRFs作用的蛋白质组学分析，受影响最大的途径富集在线粒体代谢中。一致地，在神经元坏死中，线粒体碎片化增加，并且通过基因操作或药物抑制线粒体分裂可挽救神经元坏死。利用我们先前建立的果蝇神经元坏死模型，我们发现抑制小RNA转录、阻断RNA从细胞核到细胞质的运输，或者敲低Ago1/2以抑制RNA干扰效应，都挽救了果蝇的死亡，这表明小RNA的转录和加工有助于神经元坏死。总之，这些结果表明tRFs的异常转录可能在H3K4me3增加的下游起关键作用。这为抑制神经元坏死提供了一种潜在的新策略。
Neuronal necrosis induced by excessive glutamate release is well known to contribute morbidity and mortality in ischemic stroke. Over the past decades, strategies on targeting glutamate receptor did not achieve desirable clinical outcomes. Finding the downstream mechanism of the glutamate receptor activation may provide new targets to suppress the cell death. Previously, our study demonstrated that the increase of H3K4 trimethylation (H3K4me3) played a key detrimental role on neuronal necrosis; however, the mechanism of this histone modification is unclear. Through a genome-wide small RNA sequencing, we identified several tRNA-derived fragments (tRFs) and piwi-interacting RNA (piRNAs) species were enriched in glutamate-induced neuronal necrosis in rat primary neuron cultures, and this enrichment was dependent on the H3K4me3 increase. Strikingly, when we transfected several synthesized tRFs and piRNA species into neurons, the tRFs but not the piRNAs induced neuron swelling and death. The cell death morphology recapitulated neuronal necrosis induced by glutamate. For the cytotoxic effect of tRFs, our data suggested that protein synthesis was inhibited likely through induction of ribosomal stalling. By proteomic analysis of tRFs effect, the most affected pathway was enriched in the mitochondrial metabolism. Consistently, mitochondrial fragmentation was increased in neuronal necrosis, and suppression of mitochondrial fission by genetic manipulation or drug rescued neuronal necrosis. Using our previously establishedDrosophilamodel of neuronal necrosis, we found that inhibition of small RNA transcription, blocking RNA transport from nucleus to cytosol, or knocking downAgo1/2to suppress the RNA interference effect, all rescued the fly death, suggesting transcription and processing of small RNAs contribute to neuronal necrosis. Together, these results indicate that the abnormal transcription of tRFs may play a key role downstream of the H3K4me3 increase. This provides a potential new strategy to suppress neuronal necrosis.
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影响因子：
3.5
作者：
Agrawal SA;Burgoyne T;Eblimit A;Bellingham J;Parfitt DA;Lane A;Nichols R;Asomugha C;Hayes MJ;Munro PM;Xu M;Wang K;Futter CE;Li Y;Chen R;Cheetham ME
通讯作者：
Cheetham ME
影响因子：
3.5
作者：
de Goede P;Wefers J;Brombacher EC;Schrauwen P;Kalsbeek A
通讯作者：
Kalsbeek A
影响因子：
4.5
作者：
Haussecker, Dirk;Huang, Yong;Kay, Mark A.
通讯作者：
Kay, Mark A.
DOI：
10.1097/nen.0b013e3182309ab1
发表时间：
2011-10-01
影响因子：
3.2
作者：
De Nuccio, Chiara;Bernardo, Antonietta;Minghetti, Luisa
通讯作者：
Minghetti, Luisa
影响因子：
48
作者：
Hill, Michael D.;Martin, Renee H.;Tymianski, Michael
通讯作者：
Tymianski, Michael