Panoramic Visualization of Circulating MicroRNAs Across Neurodegenerative Diseases in Humans
Panoramic Visualization of Circulating MicroRNAs Across Neurodegenerative Diseases in Humans
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DOI：
10.1007/s12035-019-1615-1
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发表时间：
2019-11-01
影响因子：
5.1
通讯作者：
Saksena, Nitin K.
中科院分区：
文献类型：
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作者：
Brennan, Samuel;Keon, Matthew;Saksena, Nitin K.
阿尔茨海默病(AD)、帕金森病(PD)、多发性硬化症(MS)、肌萎缩侧索硬化症(ALS)和痴呆症等神经退行性疾病(NDS)是本世纪人类面临的最大健康挑战之一。虽然这些NDS一直被视为单一实体，但到目前为止，潜在的分子机制从未被集体可视化。随着高通量基因组和蛋白质组技术的出现，我们现在有机会从一个全新的角度来看待这些疾病，这将使我们清楚地了解在最终解决这些疾病方面至关重要的主要和次要事件，指导我们制定新的治疗策略，可能同时治疗这些疾病。我们创建了所有已知在ND患者的不同体液中差异表达的microRNAs的知识库。然后，我们使用几种生物信息学方法来了解AD、PD、ALS和MS之间的功能交叉和差异。这些结果为AD、PD、MS和ALS之间可能的功能交叉提供了一个独特的全景图，在microRNA水平上，以及它们的同源基因和通路，以及统一和分离它们的实体。虽然每个ND都有明显的microRNA特征，但我们研究中唯一观察到的是hsa-miR-30b-5p在所有四个ND之间重叠，并在NDS中具有显著的功能作用。此外，我们的结果还显示了miRNAs功能趋同的证据，这与它们在包括脂肪酸合成和代谢、ECM受体相互作用、Pron疾病以及几个对神经元分化和生存至关重要的信号通路中所代表的同源基因的调控有关，这支持了它们在NDS中的相关性。设想这组NDS在一起使我们能够提出新的方法来利用循环的miRNAs作为生物标记物，并更全面地可视化不同的NDS。通过发现与ND相关的miRNAs、重叠的miRNAs以及与神经退变过程密切相关的重要通路上microRNAs的功能收敛而获得的关键分子见解，在识别新一代生物标记物以及将miRNAs发展为治疗学方面具有巨大的价值。
Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and dementia pose one of the greatest health challenges this century. Although these NDs have been looked at as single entities, the underlying molecular mechanisms have never been collectively visualized to date. With the advent of high-throughput genomic and proteomic technologies, we now have the opportunity to visualize these diseases in a whole new perspective, which will provide a clear understanding of the primary and secondary events vital in achieving the final resolution of these diseases guiding us to new treatment strategies to possibly treat these diseases together. We created a knowledge base of all microRNAs known to be differentially expressed in various body fluids of ND patients. We then used several bioinformatic methods to understand the functional intersections and differences between AD, PD, ALS, and MS. These results provide a unique panoramic view of possible functional intersections between AD, PD, MS, and ALS at the level of microRNA and their cognate genes and pathways, along with the entities that unify and separate them. While the microRNA signatures were apparent for each ND, the unique observation in our study was that hsa-miR-30b-5p overlapped between all four NDS, and has significant functional roles described across NDs. Furthermore, our results also show the evidence of functional convergence of miRNAs which was associated with the regulation of their cognate genes represented in pathways that included fatty acid synthesis and metabolism, ECM receptor interactions, prion diseases, and several signaling pathways critical to neuron differentiation and survival, underpinning their relevance in NDs. Envisioning this group of NDs together has allowed us to propose new ways of utilizing circulating miRNAs as biomarkers and in visualizing diverse NDs more holistically . The critical molecular insights gained through the discovery of ND-associated miRNAs, overlapping miRNAs, and the functional convergence of microRNAs on vital pathways strongly implicated in neurodegenerative processes can prove immensely valuable in the identifying new generation of biomarkers, along with the development of miRNAs into therapeutics.