Captive ERVWE1 triggers impairment of 5-HT neuronal plasticity in the first-episode schizophrenia by post-transcriptional activation of HTR1B in ALKBH5-m6A dependent epigenetic mechanisms

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Abstract

Background

Abnormalities in the 5-HT system and synaptic plasticity are hallmark features of schizophrenia. Previous studies suggest that the human endogenous retrovirus W family envelope (ERVWE1) is an influential risk factor for schizophrenia and inversely correlates with 5-HT4 receptor in schizophrenia. To our knowledge, no data describes the effect of ERVWE1 on 5-HT neuronal plasticity. N6-methyladenosine (m6A) regulates gene expression and impacts synaptic plasticity. Our research aims to systematically investigate the effects of ERVWE1 on 5-HT neuronal plasticity through m6A modification in schizophrenia.

Results

HTR1B, ALKBH5, and Arc exhibited higher levels in individuals with first-episode schizophrenia compared to the controls and showed a strong positive correlation with ERVWE1. Interestingly, HTR1B was also correlated with ALKBH5 and Arc. Further analyses confirmed that ALKBH5 may be an independent risk factor for schizophrenia. In vitro studies, we discovered that ERVWE1 enhanced HTR1B expression, thereby activating the ERK-ELK1-Arc pathway and reducing the complexity and spine density of 5-HT neurons. Furthermore, ERVWE1 reduced m6A levels through ALKBH5 demethylation. ERVWE1 induced HTR1B upregulation by improving its mRNA stability in ALKBH5-m6A-dependent epigenetic mechanisms. Importantly, ALKBH5 mediated the observed alterations in 5-HT neuronal plasticity induced by ERVWE1.

Conclusions

Overall, HTR1B, Arc, and ALKBH5 levels were increased in schizophrenia and positively associated with ERVWE1. Moreover, ALKBH5 was a novel risk gene for schizophrenia. ERVWE1 impaired 5-HT neuronal plasticity in ALKBH5-m6A dependent mechanism by the HTR1B-ERK-ELK1-Arc pathway, which may be an important contributor to aberrant synaptic plasticity in schizophrenia.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13578-023-01167-4.

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Most cited references 115

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Biological Insights From 108 Schizophrenia-Associated Genetic Loci

Stephan Ripke, Benjamin M. Neale, Aiden Corvin … (2015)

Summary Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.

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m6A-dependent regulation of messenger RNA stability

Xiao Wang, Zhike Lu, Adrián Gómez-Brandón … (2013)

N6 -methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA (mRNA) of all higher eukaryotes 1,2 . Although essential to cell viability and development 3–5 , the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease 6–8 . Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies 9 . The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA whereas the N-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selective-binding proteins to affect the translation status and lifetime of mRNA.

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ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

Guanqun Zheng, John Dahl, Yamei Niu … (2013)

N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m(6)A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m(6)A modification has fundamental and broad functions in mammalian cells. Copyright © 2013 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Fan Zhu:

ORCID: http://orcid.org/0000-0001-7031-2956

fanzhu@whu.edu.cn

Journal

Journal ID (nlm-ta): Cell Biosci

Journal ID (iso-abbrev): Cell Biosci

Title: Cell & Bioscience

Publisher: BioMed Central (London )

ISSN (Electronic): 2045-3701

Publication date (Electronic): 21 November 2023

Publication date PMC-release: 21 November 2023

Publication date Collection: 2023

Volume: 13

Electronic Location Identifier: 213

Affiliations

[1 ]State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, ( https://ror.org/033vjfk17) Wuhan, 430071 China

[2 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Wuhan Mental Health Center, ; Wuhan, 430071 China

[3 ]Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, ( https://ror.org/033vjfk17) Wuhan, 430071 China

Author information

Fan Zhu http://orcid.org/0000-0001-7031-2956

Article

Publisher ID: 1167

DOI: 10.1186/s13578-023-01167-4

PMC ID: 10664518

PubMed ID: 37990254

SO-VID: 86681aa3-8138-47f6-ac0f-345734d35bba

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 27 July 2023

Date accepted : 7 November 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82272321

Award ID: 81971943

Award Recipient : Fan Zhu

Funded by: FundRef http://dx.doi.org/10.13039/501100012226, Fundamental Research Funds for the Central Universities;

Award ID: 2042023kf0230

Award Recipient : Fan Zhu

Funded by: FundRef http://dx.doi.org/10.13039/100012224, Stanley Foundation;

Award ID: 06R-1366

Award Recipient : Fan Zhu

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ScienceOpen disciplines: Cell biology

Keywords: schizophrenia,ervwe1,htr1b,alkbh5,synaptic plasticity

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ScienceOpen disciplines: Cell biology

Keywords: schizophrenia, ervwe1, htr1b, alkbh5, synaptic plasticity

Captive ERVWE1 triggers impairment of 5-HT neuronal plasticity in the first-episode schizophrenia by post-transcriptional activation of HTR1B in ALKBH5-m6A dependent epigenetic mechanisms

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Most cited references 115

Biological Insights From 108 Schizophrenia-Associated Genetic Loci

m6A-dependent regulation of messenger RNA stability

ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

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