Abstract
BackgroundAging 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.MethodsHuman 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.ResultsEPB41L4A-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.ConclusionsDownregulation 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.
Highlights
Long non-coding RNAs are a class of noncoding RNAs usually longer than 200 nucleotides in length [1]
Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases
EPB41L4A-AS1 was first reported as a protein-coding gene named TIGA1 related to cell proliferation [9]; later studies demonstrated that EPB41L4A-AS1 mainly functioned as a Long noncoding RNA (lncRNA) associated with cell metabolism and immune response [7, 10, 11], and its downregulation in cancer cells induced glutamine dependency and promoted glycolysis [7]
Summary
Long non-coding RNAs (lncRNAs) are a class of noncoding RNAs usually longer than 200 nucleotides in length [1]. LncRNAs have been regarded as useless cell components; in recent years, an increasing number of studies have shown that lncRNAs played important regulatory roles in cells. LncRNAs have been documented to play an important regulatory role in cell metabolism, including glycolysis [7] and Aβ clearance [8]. EPB41L4A-AS1 was first reported as a protein-coding gene named TIGA1 related to cell proliferation [9]; later studies demonstrated that EPB41L4A-AS1 mainly functioned as a lncRNA associated with cell metabolism and immune response [7, 10, 11], and its downregulation in cancer cells induced glutamine dependency and promoted glycolysis [7]. As a metabolismrelated long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. We sought to reveal the mechanisms of EPB41L4A-AS in aging and neurodegenerative diseases
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