Pooja Kri Gupta, Sharon Barak, Yonatan Feuermann, Gil Goobes, Hanoch Kaphzan
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Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development.</p><p><strong>Methods: </strong>We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance (<sup>1</sup>H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis.</p><p><strong>Results: </strong>Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways.</p><p><strong>Limitations: </strong>Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. Furthermore, increasing the sample size could reveal the involvement of more significantly altered metabolites in the pathophysiology of the AS brain.</p><p><strong>Conclusions: </strong>Ube3a loss of function alters bioenergy-related metabolism in the AS brain during embryonic development. Furthermore, these neurochemical changes could be linked to the mitochondrial reactive oxygen species and oxidative stress that occurs during the AS embryonic development.</p>","PeriodicalId":18733,"journal":{"name":"Molecular Autism","volume":null,"pages":null},"PeriodicalIF":6.3000,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267930/pdf/","citationCount":"0","resultStr":"{\"title\":\"<sup>1</sup>H-NMR-based metabolomics reveals metabolic alterations in early development of a mouse model of Angelman syndrome.\",\"authors\":\"Pooja Kri Gupta, Sharon Barak, Yonatan Feuermann, Gil Goobes, Hanoch Kaphzan\",\"doi\":\"10.1186/s13229-024-00608-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Angelman syndrome (AS) is a rare neurodevelopmental genetic disorder caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, affecting approximately 1:15,000 live births. We have recently shown that mitochondrial function in AS is altered during mid to late embryonic brain development leading to increased oxidative stress and enhanced apoptosis of neural precursor cells. However, the overall alterations of metabolic processes are still unknown. Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development.</p><p><strong>Methods: </strong>We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance (<sup>1</sup>H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis.</p><p><strong>Results: </strong>Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways.</p><p><strong>Limitations: </strong>Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. 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引用次数: 0
摘要
背景:安杰尔曼综合征(AS)是一种罕见的神经发育遗传性疾病,由泛素连接酶 E3A(UBE3A)基因功能缺失引起,约有 1:15,000 的活产儿患病。我们最近发现,在胚胎中后期的大脑发育过程中,AS 的线粒体功能会发生改变,导致氧化应激增加和神经前体细胞凋亡增强。然而,新陈代谢过程的整体改变仍是未知数。因此,作为后续研究,我们旨在调查野生型(WT)和AS同窝鼠的代谢概况,并确定AS模型小鼠在胚胎发育期间大脑中哪些代谢过程出现异常:我们收集了小鼠胚胎发育至16.5岁时的脑组织样本,并使用质子核磁共振(1H-NMR)光谱进行了代谢组学分析。通过多变量和单变量分析,确定强直性脊柱炎小鼠体内发生显著改变的代谢物。利用代谢物集富集分析确定了与代谢物改变相关的通路:结果:我们的分析表明,AS胚胎大脑的代谢组指纹总体上与WT同窝鼠不同。此外,与 WT 样本相比,我们发现 AS 样本中乙酸盐、乳酸盐和琥珀酸盐等代谢物明显升高。代谢物的升高与丙酮酸代谢和糖酵解途径密切相关:局限性:本研究仅成功鉴定并调查了 14 种代谢物。局限性:本研究只成功鉴定和调查了 14 种代谢物,未确定未鉴定代谢物及其未解析峰的影响。此外,我们对整个脑组织样本进行了代谢组学研究。对不同脑区进行高分辨率核磁共振研究可进一步扩展我们对 AS 脑代谢改变的认识。此外,增加样本量可以揭示更多明显改变的代谢物参与了强直性脊柱炎大脑的病理生理学:结论:Ube3a功能缺失会改变AS大脑胚胎发育过程中与生物能相关的代谢。此外,这些神经化学变化可能与强直性脊柱炎胚胎发育过程中出现的线粒体活性氧和氧化应激有关。
1H-NMR-based metabolomics reveals metabolic alterations in early development of a mouse model of Angelman syndrome.
Background: Angelman syndrome (AS) is a rare neurodevelopmental genetic disorder caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, affecting approximately 1:15,000 live births. We have recently shown that mitochondrial function in AS is altered during mid to late embryonic brain development leading to increased oxidative stress and enhanced apoptosis of neural precursor cells. However, the overall alterations of metabolic processes are still unknown. Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development.
Methods: We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis.
Results: Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways.
Limitations: Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. Furthermore, increasing the sample size could reveal the involvement of more significantly altered metabolites in the pathophysiology of the AS brain.
Conclusions: Ube3a loss of function alters bioenergy-related metabolism in the AS brain during embryonic development. Furthermore, these neurochemical changes could be linked to the mitochondrial reactive oxygen species and oxidative stress that occurs during the AS embryonic development.
期刊介绍:
Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.