Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP

Abstract Background Aging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. In this study, we sought to reveal...

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Autores principales:	Tingpeng Yang, Yanzhi Wang, Weijie Liao, Shikuan Zhang, Songmao Wang, Naihan Xu, Weidong Xie, Cheng Luo, Yangyang Wang, Ziqiang Wang, Yaou Zhang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Aging Neurodegenerative diseases EPB41L4A- AS1 NAD+ ATP H3K27Ac Biotechnology TP248.13-248.65 Biology (General) QH301-705.5 Biochemistry QD415-436
Acceso en línea:	https://doaj.org/article/caaac27d0d3f4084bc0bf300daa4794e
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spelling	oai:doaj.org-article:caaac27d0d3f4084bc0bf300daa4794e2021-11-14T12:31:43ZDown-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP10.1186/s13578-021-00705-22045-3701https://doaj.org/article/caaac27d0d3f4084bc0bf300daa4794e2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13578-021-00705-2https://doaj.org/toc/2045-3701Abstract Background Aging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. In this study, we sought to reveal the mechanisms of EPB41L4A-AS in aging and neurodegenerative diseases. Methods Human hippocampal gene expression profiles downloaded from the Genotype-Tissue Expression database were analyzed to obtain age-stratified differentially expressed genes; a weighted correlation network analysis algorithm was then used to construct a gene co-expression network of these differentially expressed genes to obtain gene clustering modules. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction network, and correlation analysis were used to reveal the role of EPB41L4A-AS1. The mechanism was verified using Gene Expression Omnibus dataset GSE5281 and biological experiments (construction of cell lines, Real-time quantitative PCR, Western blot, measurement of ATP and NAD+ levels, nicotinamide riboside treatment, Chromatin Immunoprecipitation) in neurons and glial-derived cells. Results EPB41L4A-AS1 was downregulated in aging and Alzheimer's disease. EPB41L4A-AS1 related genes were found to be enriched in the electron transport chain and NAD+ synthesis pathway. Furthermore, these genes were highly associated with neurodegenerative diseases and positively correlated with EPB41L4A-AS1. In addition, biological experiments proved that the downregulation of EPB41L4A-AS1 could reduce the expression of these genes via histone H3 lysine 27 acetylation, resulting in decreased NAD+ and ATP levels, while EPB41L4A-AS1 overexpression and nicotinamide riboside treatment could restore the NAD+ and ATP levels. Conclusions Downregulation of EPB41L4A-AS1 not only disturbs NAD+ biosynthesis but also affects ATP synthesis. As a result, the high demand for NAD+ and ATP in the brain cannot be met, promoting the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD+ synthesis, can reduce EPB41L4A-AS1 downregulation-mediated decrease of NAD+ and ATP synthesis. Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases.Tingpeng YangYanzhi WangWeijie LiaoShikuan ZhangSongmao WangNaihan XuWeidong XieCheng LuoYangyang WangZiqiang WangYaou ZhangBMCarticleAgingNeurodegenerative diseasesEPB41L4A- AS1NAD+ATPH3K27AcBiotechnologyTP248.13-248.65Biology (General)QH301-705.5BiochemistryQD415-436ENCell & Bioscience, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aging Neurodegenerative diseases EPB41L4A- AS1 NAD+ ATP H3K27Ac Biotechnology TP248.13-248.65 Biology (General) QH301-705.5 Biochemistry QD415-436
spellingShingle	Aging Neurodegenerative diseases EPB41L4A- AS1 NAD+ ATP H3K27Ac Biotechnology TP248.13-248.65 Biology (General) QH301-705.5 Biochemistry QD415-436 Tingpeng Yang Yanzhi Wang Weijie Liao Shikuan Zhang Songmao Wang Naihan Xu Weidong Xie Cheng Luo Yangyang Wang Ziqiang Wang Yaou Zhang Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP
description	Abstract Background Aging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. In this study, we sought to reveal the mechanisms of EPB41L4A-AS in aging and neurodegenerative diseases. Methods Human hippocampal gene expression profiles downloaded from the Genotype-Tissue Expression database were analyzed to obtain age-stratified differentially expressed genes; a weighted correlation network analysis algorithm was then used to construct a gene co-expression network of these differentially expressed genes to obtain gene clustering modules. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction network, and correlation analysis were used to reveal the role of EPB41L4A-AS1. The mechanism was verified using Gene Expression Omnibus dataset GSE5281 and biological experiments (construction of cell lines, Real-time quantitative PCR, Western blot, measurement of ATP and NAD+ levels, nicotinamide riboside treatment, Chromatin Immunoprecipitation) in neurons and glial-derived cells. Results EPB41L4A-AS1 was downregulated in aging and Alzheimer's disease. EPB41L4A-AS1 related genes were found to be enriched in the electron transport chain and NAD+ synthesis pathway. Furthermore, these genes were highly associated with neurodegenerative diseases and positively correlated with EPB41L4A-AS1. In addition, biological experiments proved that the downregulation of EPB41L4A-AS1 could reduce the expression of these genes via histone H3 lysine 27 acetylation, resulting in decreased NAD+ and ATP levels, while EPB41L4A-AS1 overexpression and nicotinamide riboside treatment could restore the NAD+ and ATP levels. Conclusions Downregulation of EPB41L4A-AS1 not only disturbs NAD+ biosynthesis but also affects ATP synthesis. As a result, the high demand for NAD+ and ATP in the brain cannot be met, promoting the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD+ synthesis, can reduce EPB41L4A-AS1 downregulation-mediated decrease of NAD+ and ATP synthesis. Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases.
format	article
author	Tingpeng Yang Yanzhi Wang Weijie Liao Shikuan Zhang Songmao Wang Naihan Xu Weidong Xie Cheng Luo Yangyang Wang Ziqiang Wang Yaou Zhang
author_facet	Tingpeng Yang Yanzhi Wang Weijie Liao Shikuan Zhang Songmao Wang Naihan Xu Weidong Xie Cheng Luo Yangyang Wang Ziqiang Wang Yaou Zhang
author_sort	Tingpeng Yang
title	Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP
title_short	Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP
title_full	Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP
title_fullStr	Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP
title_full_unstemmed	Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP
title_sort	down-regulation of epb41l4a-as1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of nad+ and atp
publisher	BMC
publishDate	2021
url	https://doaj.org/article/caaac27d0d3f4084bc0bf300daa4794e
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Down-regulation of EPB41L4A-AS1 mediated the brain aging and neurodegenerative diseases via damaging synthesis of NAD+ and ATP

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