Department of Biological Sciences Bose Institute, Unified Academic Campus. EN-80, Sector V, Bidhan Nagar, Kolkata- 700091, West Bengal, India.
Department of Pharmaceutical Science and Technology, Maulana Abul Kalam Azad University of Technology, Nadia, Haringhata, 741249, India.
Curr Alzheimer Res. 2023;20(8):539-556. doi: 10.2174/0115672050261526231013095933.
Alzheimer's disease is the most common neurodegenerative disorder. Recent development in sciences has also identified the pivotal role of microRNAs (miRNAs) in AD pathogenesis.
We proposed a novel method to identify AD pathway-specific statistically significant miRNAs from the targets of known AD drugs. Moreover, microRNA scaffolds and corresponding drug scaffolds of different pathways were also discovered.
A Wilcoxon signed-rank test was performed to identify pathway-specific significant miRNAs. We generated feed-forward loop regulations of microRNA-TF-gene-based networks, studied the minimum free energy structures of pre-microRNA sequences, and clustered those microRNAs with their corresponding structural motifs of robust transcription factors. Conservation analyses of significant microRNAs were done, and the phylogenetic trees were constructed. We identified 3'UTR binding sites and chromosome locations of these significant microRNAs.
In this study, hsa-miR-4261, hsa-miR-153-5p, hsa-miR-6766, and hsa-miR-4319 were identified as key miRNAs for the ACHE pathway and hsa-miR-326, hsa-miR-6133, hsa-miR-4251, hsa-miR-3148, hsa-miR-10527-5p, hsa-miR-527, and hsa-miR-518a were identified as regulatory miRNAs for the NMDA pathway. These miRNAs were regulated by several AD-specific TFs, namely RAD21, FOXA1, and ESR1. It has been observed that anisole and adamantane are important chemical scaffolds to regulate these significant miRNAs.
This is the first study that developed a detailed correlation between known AD drug scaffolds and their AD target-specific miRNA scaffolds. This study identified chromosomal locations of microRNAs and corresponding structural scaffolds of transcription factors that may be responsible for miRNA co-regulation for Alzheimer's disease. Our study provides hope for therapeutic improvements in the existing microRNAs by regulating pathways and targets.
阿尔茨海默病是最常见的神经退行性疾病。科学的最新发展也确定了 microRNAs（miRNAs）在 AD 发病机制中的关键作用。
我们提出了一种从已知 AD 药物靶点中识别 AD 通路特异性统计上显著 miRNAs 的新方法。此外，还发现了 miRNA 支架和不同通路的相应药物支架。
采用 Wilcoxon 符号秩检验识别通路特异性显著 miRNAs。我们生成了基于 miRNA-TF-基因的前馈环调控网络，研究了 pre-miRNA 序列的最小自由能结构，并对具有稳健转录因子结构基序的 miRNA 进行了聚类。对显著 miRNAs 进行了保守性分析，并构建了系统发育树。我们确定了这些显著 miRNAs 的 3'UTR 结合位点和染色体位置。
在这项研究中，hsa-miR-4261、hsa-miR-153-5p、hsa-miR-6766 和 hsa-miR-4319 被鉴定为 ACHE 通路的关键 miRNAs，hsa-miR-326、hsa-miR-6133、hsa-miR-4251、hsa-miR-3148、hsa-miR-10527-5p、hsa-miR-527 和 hsa-miR-518a 被鉴定为 NMDA 通路的调节 miRNAs。这些 miRNAs 受几个 AD 特异性 TF（即 RAD21、FOXA1 和 ESR1）调控。已经观察到，苯甲醚和金刚烷是调节这些显著 miRNAs 的重要化学支架。
这是第一项开发已知 AD 药物支架与其 AD 靶标特异性 miRNA 支架之间详细相关性的研究。这项研究确定了微 RNA 的染色体位置和相应转录因子的结构支架，这些可能是负责阿尔茨海默病 miRNA 共调控的原因。我们的研究为通过调节途径和靶点来改善现有微 RNA 的治疗提供了希望。
