肌萎缩性脊髓侧索硬化症患者体内上调的 miR-10b-5p 是一种潜在的 miRNA 标志。

IF 4.2 3区 医学 Q2 NEUROSCIENCES
Frontiers in Cellular Neuroscience Pub Date : 2024-11-07 eCollection Date: 2024-01-01 DOI:10.3389/fncel.2024.1457704
Banaja P Dash, Axel Freischmidt, Anika M Helferich, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt, Andreas Hermann
{"title":"肌萎缩性脊髓侧索硬化症患者体内上调的 miR-10b-5p 是一种潜在的 miRNA 标志。","authors":"Banaja P Dash, Axel Freischmidt, Anika M Helferich, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt, Andreas Hermann","doi":"10.3389/fncel.2024.1457704","DOIUrl":null,"url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived <i>SOD1</i>- and <i>TARDBP</i> (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1457704"},"PeriodicalIF":4.2000,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586771/pdf/","citationCount":"0","resultStr":"{\"title\":\"Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.\",\"authors\":\"Banaja P Dash, Axel Freischmidt, Anika M Helferich, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt, Andreas Hermann\",\"doi\":\"10.3389/fncel.2024.1457704\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived <i>SOD1</i>- and <i>TARDBP</i> (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.</p>\",\"PeriodicalId\":12432,\"journal\":{\"name\":\"Frontiers in Cellular Neuroscience\",\"volume\":\"18 \",\"pages\":\"1457704\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-11-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586771/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in Cellular Neuroscience\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3389/fncel.2024.1457704\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Cellular Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fncel.2024.1457704","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

摘要

肌萎缩性脊髓侧索硬化症(ALS)是一种致命的成人发病性疾病,其特征是脊髓、脑干和运动皮层中的运动神经元(MNs)发生进行性变性。大多数患者通常在发病后 2-4 年内死亡。尽管在研究蛋白质稳态紊乱、DNA/RNA 代谢、剪接或适当的核细胞质穿梭等潜在机制方面取得了令人鼓舞的进展,但绝大多数病例仍没有有效的治疗方法。其中一个原因可能是疾病的异质性以及缺乏实质性的临床和分子生物标志物。鉴定和验证这类病理生理学驱动的生物标志物有助于早期诊断和治疗分层。下一代 RNA 测序方法的最新进展为确定与 ALS 疾病相关的非编码 RNA(ncRNA)的关键变化提供了重要见解。特别是微小 RNA(miRNA)已成为基因表达的关键转录后调控因子,通过降解信使 RNA(mRNA)或抑制基因表达水平来靶向多个基因/通路。在这项研究中,我们扩展了之前的工作,通过结合不同的归一化方法来识别最高调控的差异表达(DE)-miRNA,以寻找 ALS 中重要的、可推广的病理机制失调,作为该疾病的潜在新型生物标志物。为此,我们对现有数据集进行了共识流水线分析,研究了从 iPSC 衍生的 SOD1 和 TARDBP(TDP-43 蛋白)-mutant-ALS 患者和健康对照者的 MN 细胞系的转录组图谱(mRNA 和 miRNA),以确定与神经变性相关的潜在特征及其相关通路。ALS 患者的 MN 细胞系中 miRNA 与 MRNA 相互作用的转录谱分析显示,不同基因的表达更容易受到 KEAP1-NRF2 应激反应通路的影响,这与这两种疾病有共同的分子特征。我们还报告说,上述基因的突变导致了候选的 miR-10b-5p 的显著上调,我们可以在来自散发性和家族性 ALS 患者的永生化淋巴母细胞系(LCLs)以及家族性 ALS 患者的死后组织中验证这一点。总之,我们的研究结果表明,同时对各种人体生物样本进行 miRNA 分析,可能会发现共同的 miRNA 图谱,这些图谱有可能成为该病的生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
7.90
自引率
3.80%
发文量
627
审稿时长
6-12 weeks
期刊介绍: Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信