在Angelman综合征小鼠模型中,膳食摄入辛酸可恢复UBE3A表达并改善行为表型

IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Song Qu, Xingying Guan, Hongyan Li, Jian Yang, Pu Sun, Cui Song, Natalia Surzenko, Yanyan Wang
{"title":"在Angelman综合征小鼠模型中,膳食摄入辛酸可恢复UBE3A表达并改善行为表型","authors":"Song Qu,&nbsp;Xingying Guan,&nbsp;Hongyan Li,&nbsp;Jian Yang,&nbsp;Pu Sun,&nbsp;Cui Song,&nbsp;Natalia Surzenko,&nbsp;Yanyan Wang","doi":"10.1096/fj.202403130RR","DOIUrl":null,"url":null,"abstract":"<p>Angelman syndrome (AS) is a severe neurodevelopmental disorder with no effective therapies. Most of the behavioral deficits observed in AS patients arise from the absence of ubiquitin protein ligase E3A (UBE3A) in the brain during development, driven by the loss of maternally expressed <i>UBE3A</i> and silencing of the paternal copy of this gene through imprinting. Safe and effective therapies aiming at restoring the expression of the paternal <i>UBE3A</i> gene early in human life are currently lacking. In this study, we investigated whether octanoic acid (OA), a medium-chain fatty acid, could unsilence the paternal <i>Ube3a</i> allele in neurons and ameliorate the behavioral defects in a murine model of AS. To this end, <i>Ube3a</i><sup><i>m−/p+</i></sup> and <i>Ube3a</i><sup><i>m+/pYFP</i></sup> mice, as well as their wild-type littermates, were fed either a control or OA-supplemented diet from postnatal day 0 through adulthood, and the improvements in AS-related cellular and behavioral deficits were characterized. We demonstrate that dietary intake of OA activates the expression of the silenced, paternal <i>Ube3a</i> in neurons and improves select AS behavioral phenotypes in mice. We further show that downregulation of topoisomerase II beta and restoration of dendritic spine development may underlie the unsilencing of <i>Ube3a</i> and the behavioral improvements in OA-supplemented animals, respectively. Together, our findings suggest that dietary supplementation with OA could serve as an early, safe, and clinically feasible therapeutic strategy for reactivation of the paternal <i>UBE3A</i> allele in patients with AS.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403130RR","citationCount":"0","resultStr":"{\"title\":\"Dietary Intake of Octanoic Acid Restores UBE3A Expression and Improves the Behavioral Phenotypes in a Mouse Model of Angelman Syndrome\",\"authors\":\"Song Qu,&nbsp;Xingying Guan,&nbsp;Hongyan Li,&nbsp;Jian Yang,&nbsp;Pu Sun,&nbsp;Cui Song,&nbsp;Natalia Surzenko,&nbsp;Yanyan Wang\",\"doi\":\"10.1096/fj.202403130RR\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Angelman syndrome (AS) is a severe neurodevelopmental disorder with no effective therapies. Most of the behavioral deficits observed in AS patients arise from the absence of ubiquitin protein ligase E3A (UBE3A) in the brain during development, driven by the loss of maternally expressed <i>UBE3A</i> and silencing of the paternal copy of this gene through imprinting. Safe and effective therapies aiming at restoring the expression of the paternal <i>UBE3A</i> gene early in human life are currently lacking. In this study, we investigated whether octanoic acid (OA), a medium-chain fatty acid, could unsilence the paternal <i>Ube3a</i> allele in neurons and ameliorate the behavioral defects in a murine model of AS. To this end, <i>Ube3a</i><sup><i>m−/p+</i></sup> and <i>Ube3a</i><sup><i>m+/pYFP</i></sup> mice, as well as their wild-type littermates, were fed either a control or OA-supplemented diet from postnatal day 0 through adulthood, and the improvements in AS-related cellular and behavioral deficits were characterized. We demonstrate that dietary intake of OA activates the expression of the silenced, paternal <i>Ube3a</i> in neurons and improves select AS behavioral phenotypes in mice. We further show that downregulation of topoisomerase II beta and restoration of dendritic spine development may underlie the unsilencing of <i>Ube3a</i> and the behavioral improvements in OA-supplemented animals, respectively. Together, our findings suggest that dietary supplementation with OA could serve as an early, safe, and clinically feasible therapeutic strategy for reactivation of the paternal <i>UBE3A</i> allele in patients with AS.</p>\",\"PeriodicalId\":50455,\"journal\":{\"name\":\"The FASEB Journal\",\"volume\":\"39 8\",\"pages\":\"\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2025-04-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403130RR\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The FASEB Journal\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202403130RR\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The FASEB Journal","FirstCategoryId":"99","ListUrlMain":"https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202403130RR","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

Angelman综合征是一种严重的神经发育障碍,目前尚无有效的治疗方法。在AS患者中观察到的大多数行为缺陷是由于发育过程中大脑中泛素蛋白连接酶E3A (UBE3A)的缺失,这是由于母体表达的UBE3A缺失以及该基因的父本拷贝通过印记被沉默所驱动的。目前缺乏旨在恢复人类生命早期父系UBE3A基因表达的安全有效的治疗方法。在这项研究中,我们研究了中链脂肪酸辛酸(OA)是否可以解除神经元中父本Ube3a等位基因的沉默,并改善小鼠AS模型的行为缺陷。为此,Ube3am−/p+和Ube3am+/pYFP小鼠以及它们的野生型幼崽,从出生后第0天到成年,分别饲喂对照或补充oa的饮食,并观察与as相关的细胞和行为缺陷的改善。我们证明,膳食摄入OA激活了神经元中沉默的父系Ube3a的表达,并改善了小鼠的选择AS行为表型。我们进一步表明,拓扑异构酶II β的下调和树突棘发育的恢复可能分别是Ube3a的解除沉默和oa补充动物行为改善的基础。总之,我们的研究结果表明,膳食补充OA可以作为as患者父本UBE3A等位基因再激活的早期、安全、临床可行的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Dietary Intake of Octanoic Acid Restores UBE3A Expression and Improves the Behavioral Phenotypes in a Mouse Model of Angelman Syndrome

Dietary Intake of Octanoic Acid Restores UBE3A Expression and Improves the Behavioral Phenotypes in a Mouse Model of Angelman Syndrome

Dietary Intake of Octanoic Acid Restores UBE3A Expression and Improves the Behavioral Phenotypes in a Mouse Model of Angelman Syndrome

Dietary Intake of Octanoic Acid Restores UBE3A Expression and Improves the Behavioral Phenotypes in a Mouse Model of Angelman Syndrome

Dietary Intake of Octanoic Acid Restores UBE3A Expression and Improves the Behavioral Phenotypes in a Mouse Model of Angelman Syndrome

Angelman syndrome (AS) is a severe neurodevelopmental disorder with no effective therapies. Most of the behavioral deficits observed in AS patients arise from the absence of ubiquitin protein ligase E3A (UBE3A) in the brain during development, driven by the loss of maternally expressed UBE3A and silencing of the paternal copy of this gene through imprinting. Safe and effective therapies aiming at restoring the expression of the paternal UBE3A gene early in human life are currently lacking. In this study, we investigated whether octanoic acid (OA), a medium-chain fatty acid, could unsilence the paternal Ube3a allele in neurons and ameliorate the behavioral defects in a murine model of AS. To this end, Ube3am−/p+ and Ube3am+/pYFP mice, as well as their wild-type littermates, were fed either a control or OA-supplemented diet from postnatal day 0 through adulthood, and the improvements in AS-related cellular and behavioral deficits were characterized. We demonstrate that dietary intake of OA activates the expression of the silenced, paternal Ube3a in neurons and improves select AS behavioral phenotypes in mice. We further show that downregulation of topoisomerase II beta and restoration of dendritic spine development may underlie the unsilencing of Ube3a and the behavioral improvements in OA-supplemented animals, respectively. Together, our findings suggest that dietary supplementation with OA could serve as an early, safe, and clinically feasible therapeutic strategy for reactivation of the paternal UBE3A allele in patients with AS.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
The FASEB Journal
The FASEB Journal 生物-生化与分子生物学
CiteScore
9.20
自引率
2.10%
发文量
6243
审稿时长
3 months
期刊介绍: The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信