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
{"title":"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","authors":"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","doi":"10.1016/j.expneurol.2024.115128","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>ANG</em> 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’tiRNA<sup>Gly-GCC</sup>, 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’tiRNA<sup>Gly-GCC</sup> revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5’tiRNA<sup>Gly-GCC</sup> 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’tiRNA<sup>Gly-GCC</sup> 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.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"385 ","pages":"Article 115128"},"PeriodicalIF":4.6000,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Effects of ALS-associated 5’tiRNAGly-GCC on the transcriptomic and proteomic profile of primary neurons in vitro\",\"authors\":\"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\",\"doi\":\"10.1016/j.expneurol.2024.115128\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <em>ANG</em> 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’tiRNA<sup>Gly-GCC</sup>, 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’tiRNA<sup>Gly-GCC</sup> revealed predominantly downregulated RNA and protein levels, with more pronounced changes in the proteome. Over half of the downregulated mRNAs contained predicted 5’tiRNA<sup>Gly-GCC</sup> 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’tiRNA<sup>Gly-GCC</sup> 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.</div></div>\",\"PeriodicalId\":12246,\"journal\":{\"name\":\"Experimental Neurology\",\"volume\":\"385 \",\"pages\":\"Article 115128\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-12-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014488624004540\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Neurology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014488624004540","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
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.
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.