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, Xingying Guan, Hongyan Li, Jian Yang, Pu Sun, Cui Song, Natalia Surzenko, 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, Xingying Guan, Hongyan Li, Jian Yang, Pu Sun, Cui Song, Natalia Surzenko, 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}
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.
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.