METTL14 inhibits Aβ1-42-induced neuronal injury through regulating the stability of CBLN4 mRNA in Alzheimer's disease.

in Journal of bioenergetics and biomembranes by Bin Mu, Jiangpeng Jing, Ruichun Li, Chuankun Li

TLDR

  • The study found that a protein called methyltransferase-like 14 (METTL14) can help protect cells from damage caused by a protein called Aβ1-42, which is linked to Alzheimer's disease (AD). The study found that METTL14 can help make a protein called cerebellin 4 (CBLN4) more stable, which can help protect cells from damage caused by Aβ1-42. The study also found that upregulating CBLN4 can help protect cells from damage caused by Aβ1-42. The study highlights the importance of understanding how proteins like METTL14 and CBLN4 work together to protect cells from damage caused by Aβ1-42, which could lead to new treatments for AD.

Abstract

Previous studies have suggested that N6-methyladenosine (mA) modification of RNA affects fundamental aspects of RNA metabolism, and mA dysregulation is implicated in various human diseases, including Alzheimer's disease (AD). This study is designed to explore the role and mechanism of methyltransferase-like 14 (METTL14) in the pathogenesis of AD. SK-N-SH cells were treated with Aβ1-42 to establish an in vitro model of AD. Cerebellin 4 (CBLN4) and METTL14 expression levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability and apoptosis were analyzed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry assay. B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), C-caspase-3, total-caspase-3, C/EBP homologous protein (CHOP), and glucose-related protein 78 (GRP78) protein levels were determined using Western blot. Interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) levels were analyzed using ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) products were examined using special assay kits. Interaction between CBLN4 and METTL14 was verified using methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assays. CBLN4 and METTL14 expression was decreased in Aβ1-42-treated SK-N-SH cells. Upregulation of CBLN4 relieved Aβ1-42-induced SK-N-SH cell apoptosis, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress in vitro. At the molecular level, METTL14 could improve the stability and expression of CBLN4 mRNA via m6A methylation. Our findings indicated that m6A methylase METTL14-mediated upregulation of CBLN4 mRNA stability could repress Aβ1-42-triggered SK-N-SH cell injury, providing a promising therapeutic target for AD treatment.

Overview

  • The study explores the role and mechanism of methyltransferase-like 14 (METTL14) in the pathogenesis of Alzheimer's disease (AD).
  • SK-N-SH cells were treated with Aβ1-42 to establish an in vitro model of AD. Cerebellin 4 (CBLN4) and METTL14 expression levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability and apoptosis were analyzed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry assay. B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), C-caspase-3, total-caspase-3, C/EBP homologous protein (CHOP), and glucose-related protein 78 (GRP78) protein levels were determined using Western blot. Interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) levels were analyzed using ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) products were examined using special assay kits. Interaction between CBLN4 and METTL14 was verified using methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assays. CBLN4 and METTL14 expression was decreased in Aβ1-42-treated SK-N-SH cells. Upregulation of CBLN4 relieved Aβ1-42-induced SK-N-SH cell apoptosis, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress in vitro. At the molecular level, METTL14 could improve the stability and expression of CBLN4 mRNA via m6A methylation. The study aims to identify a potential therapeutic target for AD treatment.

Comparative Analysis & Findings

  • The study found that CBLN4 and METTL14 expression levels were decreased in Aβ1-42-treated SK-N-SH cells. Upregulation of CBLN4 relieved Aβ1-42-induced SK-N-SH cell apoptosis, inflammation, oxidative stress, and ER stress in vitro. At the molecular level, METTL14 could improve the stability and expression of CBLN4 mRNA via m6A methylation. These findings suggest that m6A methylase METTL14-mediated upregulation of CBLN4 mRNA stability could repress Aβ1-42-triggered SK-N-SH cell injury, providing a promising therapeutic target for AD treatment.

Implications and Future Directions

  • The study highlights the importance of m6A methylation in the pathogenesis of AD and identifies a potential therapeutic target for AD treatment. Future research should focus on the role of m6A methylation in AD pathogenesis and the development of m6A-targeted therapies. Additionally, the study suggests that METTL14 may play a crucial role in the regulation of CBLN4 expression and its involvement in AD pathogenesis. Further studies are needed to investigate the role of METTL14 in AD and its potential as a therapeutic target. Finally, the study provides insights into the molecular mechanisms underlying the protective effects of CBLN4 in AD and highlights the importance of CBLN4 in regulating cellular responses to Aβ1-42. Future research should explore the role of CBLN4 in AD pathogenesis and its potential as a therapeutic target.
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