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SMG9 缺陷对斑马鱼早衰的影响

Effect of nonsense-mediated mRNA decay factor SMG9 deficiency on premature aging in zebrafish.

机构信息

Department of Cell Biology, Oita University Faculty of Medicine, Yufu, Oita, Japan.

Department of Pediatrics, Oita University Faculty of Medicine, Yufu, Oita, Japan.

出版信息

Commun Biol. 2024 May 28;7(1):654. doi: 10.1038/s42003-024-06356-6.

DOI:10.1038/s42003-024-06356-6
PMID:38806677
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11133409/
Abstract

SMG9 is an essential component of the nonsense-mediated mRNA decay (NMD) machinery, a quality control mechanism that selectively degrades aberrant transcripts. Mutations in SMG9 are associated with heart and brain malformation syndrome (HBMS). However, the molecular mechanism underlying HBMS remains unclear. We generated smg9 mutant zebrafish (smg9) that have a lifespan of approximately 6 months or longer, allowing for analysis of the in vivo function of Smg9 in adults in more detail. smg9 zebrafish display congenital brain abnormalities and reduced cardiac contraction. Additionally, smg9 zebrafish exhibit a premature aging phenotype. Analysis of NMD target mRNAs shows a trend toward increased mRNA levels in smg9 zebrafish. Spermidine oxidase (Smox) is increased in smg9 zebrafish, resulting in the accumulation of byproducts, reactive oxygen species, and acrolein. The accumulation of smox mRNA due to NMD dysregulation caused by Smg9 deficiency leads to increased oxidative stress, resulting in premature aging.

摘要

SMG9 是无意义介导的 mRNA 降解 (NMD) 机制的一个重要组成部分，该机制是一种选择性降解异常转录本的质量控制机制。SMG9 突变与心脏和脑畸形综合征 (HBMS) 有关。然而，HBMS 的分子机制尚不清楚。我们生成了具有大约 6 个月或更长寿命的 smg9 突变斑马鱼 (smg9)，从而可以更详细地分析 Smg9 在成年斑马鱼体内的体内功能。smg9 斑马鱼显示出先天性脑异常和心脏收缩减少。此外，smg9 斑马鱼还表现出过早衰老的表型。对 NMD 靶标 mRNA 的分析显示，smg9 斑马鱼的 mRNA 水平呈上升趋势。smg9 斑马鱼中的精脒氧化酶 (Smox) 增加，导致副产物、活性氧和丙烯醛的积累。由于 Smg9 缺乏导致的 NMD 失调导致 smox mRNA 的积累，从而导致氧化应激增加，导致过早衰老。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/7daed46e640a/42003_2024_6356_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/5d6583121772/42003_2024_6356_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/12f9af494b57/42003_2024_6356_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/8d005b749c2d/42003_2024_6356_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/a5b0e95b2cd6/42003_2024_6356_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/1ce3558b1be3/42003_2024_6356_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/6bc2c6d7ab8d/42003_2024_6356_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/fa5b50fdafc3/42003_2024_6356_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/7daed46e640a/42003_2024_6356_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/5d6583121772/42003_2024_6356_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/12f9af494b57/42003_2024_6356_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/8d005b749c2d/42003_2024_6356_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/a5b0e95b2cd6/42003_2024_6356_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/1ce3558b1be3/42003_2024_6356_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/6bc2c6d7ab8d/42003_2024_6356_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/fa5b50fdafc3/42003_2024_6356_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fbd/11133409/7daed46e640a/42003_2024_6356_Fig8_HTML.jpg

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