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miR-34a-5p 作为亨廷顿病发病机制的分子枢纽。

miR-34a-5p as molecular hub of pathomechanisms in Huntington's disease.

机构信息

Institute of Human Genetics, Saarland University, Building 60, 66421, Homburg, Germany.

Chair for Clinical Bioinformatics, Saarland University, 66123, Saarbrücken, Germany.

出版信息

Mol Med. 2023 Apr 3;29(1):43. doi: 10.1186/s10020-023-00640-7.

DOI:10.1186/s10020-023-00640-7
PMID:37013480
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10295337/
Abstract

BACKGROUND

Although a pivotal role of microRNA (miRNA, miR) in the pathogenesis of Huntington's disease (HD) is increasingly recognized, the molecular functions of miRNAs in the pathomechanisms of HD await further elucidation. One of the miRNAs that have been associated with HD is miR-34a-5p, which was deregulated in the mouse R6/2 model and in human HD brain tissues.

METHODS

The aim of our study was to demonstrate interactions between miR-34a-5p and HD associated genes. By computational means we predicted 12 801 potential target genes of miR-34a-5p. An in-silico pathway analysis revealed 22 potential miR-34a-5p target genes in the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway "Huntington's disease".

RESULTS

Using our high-throughput miRNA interaction reporter assay (HiTmIR) we identified NDUFA9, TAF4B, NRF1, POLR2J2, DNALI1, HIP1, TGM2 and POLR2G as direct miR-34a-5p target genes. Direct binding of miR-34a-5p to target sites in the 3'UTRs of TAF4B, NDUFA9, HIP1 and NRF1 was verified by a mutagenesis HiTmIR assay and by determining endogenous protein levels for HIP1 and NDUFA9. STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis identified protein-protein interaction networks associated with HD like "Glutamine Receptor Signaling Pathway" and "Calcium Ion Transmembrane Import Into Cytosol".

CONCLUSION

Our study demonstrates multiple interactions between miR-34a-5p and HD associated target genes and thereby lays the ground for future therapeutic interventions using this miRNA.

摘要

背景

虽然 microRNA (miRNA，miR) 在亨廷顿病 (HD) 的发病机制中起着关键作用，但 miRNA 在 HD 发病机制中的分子功能仍有待进一步阐明。与 HD 相关的 miRNAs 之一是 miR-34a-5p，它在 R6/2 小鼠模型和人类 HD 脑组织中失调。

方法

我们的研究旨在证明 miR-34a-5p 与 HD 相关基因之间的相互作用。通过计算方法，我们预测了 miR-34a-5p 的 12801 个潜在靶基因。通过计算机途径分析，我们在 KEGG (京都基因与基因组百科全书) 途径 "亨廷顿病" 中发现了 22 个潜在的 miR-34a-5p 靶基因。

结果

我们使用高通量 miRNA 相互作用报告基因检测 (HiTmIR) 鉴定了 NDUFA9、TAF4B、NRF1、POLR2J2、DNALI1、HIP1、TGM2 和 POLR2G 为直接 miR-34a-5p 靶基因。通过突变 HiTmIR 检测和测定内源性 HIP1 和 NDUFA9 蛋白水平，验证了 miR-34a-5p 对 TAF4B、NDUFA9、HIP1 和 NRF1 3'UTR 靶位点的直接结合。STRING (用于检索相互作用基因/蛋白质的搜索工具) 分析确定了与 HD 相关的蛋白质-蛋白质相互作用网络，如 "谷氨酸受体信号通路" 和 "钙离子跨膜导入细胞质"。

结论

我们的研究表明 miR-34a-5p 与 HD 相关靶基因之间存在多种相互作用，从而为未来使用这种 miRNA 进行治疗干预奠定了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/649c9e9fdd23/10020_2023_640_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/5cbe8c8b119f/10020_2023_640_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/3336c9df3c45/10020_2023_640_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/b5974f547dbf/10020_2023_640_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/639a4ed735ad/10020_2023_640_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/649c9e9fdd23/10020_2023_640_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/5cbe8c8b119f/10020_2023_640_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/3336c9df3c45/10020_2023_640_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/b5974f547dbf/10020_2023_640_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/639a4ed735ad/10020_2023_640_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3833/10295337/649c9e9fdd23/10020_2023_640_Fig5_HTML.jpg

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