als相关5'tiRNAGly-GCC对体外原代神经元转录组学和蛋白质组学的影响

IF 4.6 2区 医学 Q1 NEUROSCIENCES
Elisabeth Jirström , Anna Matveeva , Sharada Baindoor , Paul Donovan , Qilian Ma , Elena Perez Morrissey , Ingrid Arijs , Bram Boeckx , Diether Lambrechts , Amaya Garcia-Munoz , Eugène T. Dillon , Kieran Wynne , Zheng Ying , David Matallanas , Marion C. Hogg , Jochen H.M. Prehn
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引用次数: 0

摘要

trna衍生的应激诱导RNA (tirna)是一类新的小非编码RNA,已成为细胞应激反应的重要调节因子。rna来源于应激诱导的核糖核酸酶血管生成素(ANG)对特定tRNA的切割。ANG基因的功能丧失突变与肌萎缩侧索硬化症(ALS)有关,最近在ALS患者血清样本中发现了特异性tirna水平升高。然而,在神经元应激反应和神经退行性变中,tiRNA产生的生物学作用在很大程度上仍然未知。在这里,我们研究了一种特定的tiRNA 5'tiRNAGly-GCC对神经元应激反应的全基因组调控,我们发现,在暴露于ALS相关应激的原代神经元和三种ALS小鼠模型的脊髓中,该rna上调。用5'tiRNAGly-GCC合成模拟物转染的原代神经元的全转录RNA测序和无标记质谱分析显示,RNA和蛋白质水平主要下调,蛋白质组的变化更为明显。超过一半的下调mrna含有预测的5'tiRNAGly-GCC结合位点,表明该tiRNA可能通过互补结合沉默靶基因。在蛋白质组水平上,我们观察到参与翻译起始和核糖体组装的蛋白质减少,这表明对翻译有抑制作用。总之,这些发现表明,5'tiRNAGly-GCC是一种als相关的tiRNA,其功能是微调基因表达和抑制蛋白质合成,作为ang诱导的神经元应激反应的一部分。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Effects of ALS-associated 5’tiRNAGly-GCC on the transcriptomic and proteomic profile of primary neurons in vitro

Effects of ALS-associated 5’tiRNAGly-GCC on the transcriptomic and proteomic profile of primary neurons in vitro
tRNA-derived stress-induced RNAs (tiRNAs) are a new class of small non-coding RNA that have emerged as important regulators of cellular stress responses. tiRNAs are derived from specific tRNA cleavage by the stress-induced ribonuclease angiogenin (ANG). Loss-of-function mutations in the ANG gene are linked to amyotrophic lateral sclerosis (ALS), and elevated levels of specific tiRNAs were recently identified in ALS patient serum samples. However, the biological role of tiRNA production in neuronal stress responses and neurodegeneration remains largely unknown. Here, we investigated the genome-wide regulation of neuronal stress responses by a specific tiRNA, 5’tiRNAGly-GCC, which we found to be upregulated in primary neurons exposed to ALS-relevant stresses and in the spinal cord of three ALS mouse models. Whole-transcript RNA sequencing and label-free mass spectrometry on primary neurons transfected with a synthetic mimic of 5’tiRNAGly-GCC revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5’tiRNAGly-GCC binding sites, indicating that this tiRNA may silence target genes via complementary binding. On the proteome level, we observed reduction in proteins involved in translation initiation and ribosome assembly, pointing to inhibitory effects on translation. Together, these findings suggest that 5’tiRNAGly-GCC is an ALS-associated tiRNA that functions to fine-tune gene expression and supress protein synthesis as part of an ANG-induced neuronal stress response.
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来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
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