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

Tingpeng Yang; Yanzhi Wang; Weijie Liao; Shikuan Zhang; Songmao Wang; Naihan Xu; Weidong Xie; Cheng Luo; Yangyang Wang; Ziqiang Wang; Yaou Zhang

doi:10.1186/s13578-021-00705-2

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

Cell Biosci. 2021 Nov 10;11(1):192. doi: 10.1186/s13578-021-00705-2.

Authors

Tingpeng Yang^#^{1

2}, Yanzhi Wang^#², Weijie Liao^{2

3}, Shikuan Zhang^{2

4}, Songmao Wang^{2

4}, Naihan Xu^{2

3

5}, Weidong Xie^{2

3

5}, Cheng Luo^{2

3

6}, Yangyang Wang^{2

3

5}, Ziqiang Wang⁷, Yaou Zhang^{8

9

10}

Affiliations

¹ Department of Chemical Engineering, Tsinghua University, Beijing, 100084, People's Republic of China.
² State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
³ Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
⁴ School of Life Sciences, Tsinghua University, Beijing, 100084, China.
⁵ Open FIESTA Center, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China.
⁶ Department of Biomedical Engineering, Tsinghua University, Beijing, 100084, China.
⁷ Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250062, China. wangziqiang@sdfmu.edu.cn.
⁸ State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China. zhangyo@sz.tsinghua.edu.cn.
⁹ Key Lab in Healthy Science and Technology of Shenzhen, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China. zhangyo@sz.tsinghua.edu.cn.
¹⁰ Open FIESTA Center, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China. zhangyo@sz.tsinghua.edu.cn.

^# Contributed equally.

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.

Keywords: ATP; Aging; EPB41L4A- AS1; H3K27Ac; NAD+; Neurodegenerative diseases.

Grants and funding

GJHZ20180929162002061/Shenzhen International Cooperation Research Project