期刊
LIFE SCIENCES
卷 302, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2022.120652
关键词
Alzheimer's disease; micro-RNA; Long non-coding RNA; MALAT1; Receptor tyrosine kinase
资金
- HBNI, Department of Atomic Energy, Government of India [12-RD-SIN-5.04-0101]
This article explores the role of lncRNAs in Alzheimer's disease and identifies MALAT1 as a regulator of miR-200a/26a/26b, which can protect against the disease by regulating EPHA2. This novel regulatory mechanism promises to become a significant strategy in controlling Alzheimer's disease.
Altered expressions of Receptor Tyrosine Kinases (RTK) and non-coding (nc) RNAs are known to regulate the pathophysiology of Alzheimer's disease (AD). However, specific understanding of the roles played, especially the mechanistic and functional roles, by long ncRNAs in AD is still elusive. Using mouse tissue qPCR assays we observe changes in the expression levels of 41 lncRNAs in AD mice of which only 7 genes happen to have both human orthologs and AD associations. Post validation of these 7 human lncRNA genes, MEG3 and MALAT1 shows consistent and significant decrease in AD cell, animal models and human AD brain tissues, but MALAT1 showed a more pronounced decrease. Using bioinformatics, qRT-PCR, RNA FISH and RIP techniques, we could establish MALAT1 as an interactor and regulator of miRs-200a, -26a and -26b, all of which are naturally elevated in AD. We could further show that these miRNAs target the RTK EPHA2 and several of its downstream effectors. Expectedly EPHA2 over expression protects against A beta(1-42) induced cytotoxicity. Transiently knocking down MALAT1 validates these unique regulatory facets of AD at the miRNA and protein levels. Although the idea of sponging of miRNAs by lncRNAs in other pathologies is gradually gaining credibility, this novel MALAT1- miR-200a/26a/26b - EPHA2 regulation mechanism in the context of AD pathophysiology promises to become a significant strategy in controlling the disease.
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