TRA2A-induced Upregulation of LINC00662 Regulates Blood-brain Barrier Permeability by Affecting ELK4 MRNA Stability in Alzheimer's Microenvironment

Overview

Journal RNA Biol

Specialty Molecular Biology

Date 2020 May 7

PMID 32372707

Citations 16

Authors

Qianshuo Liu

Lu Zhu

Xiaobai Liu

Jian Zheng

Yunhui Liu

Xuelei Ruan

Shuo Cao

Heng Cai

Zhen Li

Yixue Xue

Affiliations

Soon will be listed here.

Abstract

The blood-brain barrier (BBB) plays a pivotal role in the maintenance and regulation of the neural microenvironment. The BBB breakdown is a pathological change in early Alzheimer's disease (AD). RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) are involved in the regulation of BBB permeability. Our study demonstrates the role of TRA2A/LINC00662/ELK4 axis in regulating BBB permeability in AD microenvironment. In Aβ-incubated microvascular endothelial cells (ECs) of the BBB model , TRA2A and LINC00662 were enriched. TRA2A increased the stability of LINC00662 by binding with it. The knockdown of either TRA2A or LINC00662 decreased BBB permeability due to increased expression of tight junction-related proteins. ELK4 was less expressed in the BBB model in AD microenvironment . LINC00662 mediated the degradation of ELK4 mRNA by SMD pathway. Downregulation of ELK4 increased BBB permeability by increasing the tight junction-related protein expression.TRA2A/LINC00662/ELK4 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment, which may provide a novel target for the therapy of AD.

Citing Articles

SENP1 inhibits aerobic glycolysis in Aβ-incubated astrocytes by promoting PUM2 deSUMOylation.

Liu Q, Jiang M, Wang Z, Meng J, Jia H, Li J Cell Biol Toxicol. 2025; 41(1):28.

PMID: 39794619 PMC: 11723902. DOI: 10.1007/s10565-025-09986-6.

Is the Relationship Between Cardiovascular Disease and Alzheimer's Disease Genetic? A Scoping Review.

Moore A, Ritchie M Genes (Basel). 2025; 15(12).

PMID: 39766777 PMC: 11675426. DOI: 10.3390/genes15121509.

Exosomes and non-coding RNAs: bridging the gap in Alzheimer's pathogenesis and therapeutics.

Chunhui G, Yanqiu Y, Jibing C, Ning L, Fujun L Metab Brain Dis. 2025; 40(1):84.

PMID: 39754674 PMC: 11700052. DOI: 10.1007/s11011-024-01520-7.

Endothelial Dysfunctions in Blood-Brain Barrier Breakdown in Alzheimer's Disease: From Mechanisms to Potential Therapies.

Yue Q, Leng X, Xie N, Zhang Z, Yang D, Man Hoi M CNS Neurosci Ther. 2024; 30(11):e70079.

PMID: 39548663 PMC: 11567945. DOI: 10.1111/cns.70079.

Epigenetic modifications of DNA and RNA in Alzheimer's disease.

Martinez-Feduchi P, Jin P, Yao B Front Mol Neurosci. 2024; 17:1398026.

PMID: 38726308 PMC: 11079283. DOI: 10.3389/fnmol.2024.1398026.

References

Liu Y, Nie H, Liu C, Zhai X, Sang Q, Wang Y . Angulin proteins ILDR1 and ILDR2 regulate alternative pre-mRNA splicing through binding to splicing factors TRA2A, TRA2B, or SRSF1. Sci Rep. 2017; 7(1):7466. PMC: 5547134. DOI: 10.1038/s41598-017-07530-z. View

Kang M, Abdelmohsen K, Hutchison E, Mitchell S, Grammatikakis I, Guo R . HuD regulates coding and noncoding RNA to induce APP→Aβ processing. Cell Rep. 2014; 7(5):1401-1409. PMC: 4074355. DOI: 10.1016/j.celrep.2014.04.050. View

Nakagawa S, Deli M, Nakao S, Honda M, Hayashi K, Nakaoke R . Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol. 2007; 27(6):687-94. PMC: 11517186. DOI: 10.1007/s10571-007-9195-4. View

Cho H, Kim K, Han S, Choe J, Park S, Choi S . Staufen1-mediated mRNA decay functions in adipogenesis. Mol Cell. 2012; 46(4):495-506. DOI: 10.1016/j.molcel.2012.03.009. View

Yan L, Xie Y, Satyanarayanan S, Zeng H, Liu Q, Huang M . Omega-3 polyunsaturated fatty acids promote brain-to-blood clearance of β-Amyloid in a mouse model with Alzheimer's disease. Brain Behav Immun. 2019; 85:35-45. DOI: 10.1016/j.bbi.2019.05.033. View

Bestman J, Huang L, Lee-Osbourne J, Cheung P, Cline H . An in vivo screen to identify candidate neurogenic genes in the developing Xenopus visual system. Dev Biol. 2015; 408(2):269-91. PMC: 4584193. DOI: 10.1016/j.ydbio.2015.03.010. View

Liu T, Sun H, Zhu D, Dong X, Liu F, Liang X . TRA2A Promoted Paclitaxel Resistance and Tumor Progression in Triple-Negative Breast Cancers via Regulating Alternative Splicing. Mol Cancer Ther. 2017; 16(7):1377-1388. DOI: 10.1158/1535-7163.MCT-17-0026. View

de Bruin R, van der Veer E, Prins J, Lee D, Dane M, Zhang H . The RNA-binding protein quaking maintains endothelial barrier function and affects VE-cadherin and β-catenin protein expression. Sci Rep. 2016; 6:21643. PMC: 4764852. DOI: 10.1038/srep21643. View

Kossenkov A, Vachani A, Chang C, Nichols C, Billouin S, Horng W . Resection of non-small cell lung cancers reverses tumor-induced gene expression changes in the peripheral immune system. Clin Cancer Res. 2011; 17(18):5867-77. PMC: 3618688. DOI: 10.1158/1078-0432.CCR-11-0737. View

10.

Hue C, Cho F, Cao S, Dale Bass C, Meaney D, Morrison 3rd B . Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein. J Cereb Blood Flow Metab. 2015; 35(7):1191-8. PMC: 4640274. DOI: 10.1038/jcbfm.2015.38. View

11.

Ricciarelli R, Fedele E . The Amyloid Cascade Hypothesis in Alzheimer's Disease: It's Time to Change Our Mind. Curr Neuropharmacol. 2017; 15(6):926-935. PMC: 5652035. DOI: 10.2174/1570159X15666170116143743. View

12.

Moon B, Bai J, Cai M, Liu C, Shi J, Lu W . Kruppel-like factor 4-dependent Staufen1-mediated mRNA decay regulates cortical neurogenesis. Nat Commun. 2018; 9(1):401. PMC: 5785957. DOI: 10.1038/s41467-017-02720-9. View

13.

Liu W, Wang P, Shang C, Chen L, Cai H, Ma J . Endophilin-1 regulates blood-brain barrier permeability by controlling ZO-1 and occludin expression via the EGFR-ERK1/2 pathway. Brain Res. 2014; 1573:17-26. DOI: 10.1016/j.brainres.2014.05.022. View

14.

Xie L . MKL1/2 and ELK4 co-regulate distinct serum response factor (SRF) transcription programs in macrophages. BMC Genomics. 2014; 15:301. PMC: 4023608. DOI: 10.1186/1471-2164-15-301. View

15.

Su R, Cao S, Ma J, Liu Y, Liu X, Zheng J . Knockdown of SOX2OT inhibits the malignant biological behaviors of glioblastoma stem cells via up-regulating the expression of miR-194-5p and miR-122. Mol Cancer. 2017; 16(1):171. PMC: 5683208. DOI: 10.1186/s12943-017-0737-1. View

16.

Park E, Maquat L . Staufen-mediated mRNA decay. Wiley Interdiscip Rev RNA. 2013; 4(4):423-35. PMC: 3711692. DOI: 10.1002/wrna.1168. View

17.

He Q, Zhao L, Liu X, Zheng J, Liu Y, Liu L . MOV10 binding circ-DICER1 regulates the angiogenesis of glioma via miR-103a-3p/miR-382-5p mediated ZIC4 expression change. J Exp Clin Cancer Res. 2019; 38(1):9. PMC: 6323715. DOI: 10.1186/s13046-018-0990-1. View

18.

Lyu Q, Xu S, Lyu Y, Choi M, Christie C, Slivano O . stabilizes vascular endothelial cell adherens junctions through interaction with CKAP4. Proc Natl Acad Sci U S A. 2018; 116(2):546-555. PMC: 6329947. DOI: 10.1073/pnas.1810729116. View

19.

Kim Y, Furic L, DesGroseillers L, Maquat L . Mammalian Staufen1 recruits Upf1 to specific mRNA 3'UTRs so as to elicit mRNA decay. Cell. 2005; 120(2):195-208. DOI: 10.1016/j.cell.2004.11.050. View

20.

Gao L, Yu X, Chen Q, Zhou D . Alzheimer's Disease therapeutics: current and future therapies. Minerva Med. 2016; 107(2):108-13. View