Early dysregulation of GSK3β impairs mitochondrial activity in Fragile X Syndrome

IF 5.1 2区医学 Q1 NEUROSCIENCES

Neurobiology of Disease Pub Date : 2024-12-01 DOI:10.1016/j.nbd.2024.106726

Giulia Cencelli , Giorgia Pedini , Carlotta Ricci , Eleonora Rosina , Giorgia Cecchetti , Antonietta Gentile , Giuseppe Aiello , Laura Pacini , Beatrice Garrone , Rosella Ombrato , Isabella Coletta , Federica Prati , Claudio Milanese , Claudia Bagni

{"title":"Early dysregulation of GSK3β impairs mitochondrial activity in Fragile X Syndrome","authors":"Giulia Cencelli , Giorgia Pedini , Carlotta Ricci , Eleonora Rosina , Giorgia Cecchetti , Antonietta Gentile , Giuseppe Aiello , Laura Pacini , Beatrice Garrone , Rosella Ombrato , Isabella Coletta , Federica Prati , Claudio Milanese , Claudia Bagni","doi":"10.1016/j.nbd.2024.106726","DOIUrl":null,"url":null,"abstract":"<div><div>The finely tuned regulation of mitochondria activity is essential for proper brain development. Fragile X Syndrome (FXS), the leading cause of inherited intellectual disability, is a neurodevelopmental disorder in which mitochondrial dysfunction has been increasingly implicated. This study investigates the role of Glycogen Synthase Kinase 3β (GSK3β) in FXS. Several studies have reported the dysregulation of GSK3β in FXS, and its role in mitochondrial function is also well established. However, the link between disrupted GSK3β activity and mitochondrial dysfunction in FXS remains unexplored. Utilizing <em>Fmr1</em> knockout (KO) mice and human cell lines from individuals with FXS, we uncovered a developmental window where dysregulated GSK3β activity disrupts mitochondrial function. Notably, a partial inhibition of GSK3β activity in FXS fibroblasts from young individuals rescues the observed mitochondrial defects, suggesting that targeting GSK3β in the early stages may offer therapeutic benefits for this condition.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"203 ","pages":"Article 106726"},"PeriodicalIF":5.1000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Disease","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0969996124003280","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

The finely tuned regulation of mitochondria activity is essential for proper brain development. Fragile X Syndrome (FXS), the leading cause of inherited intellectual disability, is a neurodevelopmental disorder in which mitochondrial dysfunction has been increasingly implicated. This study investigates the role of Glycogen Synthase Kinase 3β (GSK3β) in FXS. Several studies have reported the dysregulation of GSK3β in FXS, and its role in mitochondrial function is also well established. However, the link between disrupted GSK3β activity and mitochondrial dysfunction in FXS remains unexplored. Utilizing Fmr1 knockout (KO) mice and human cell lines from individuals with FXS, we uncovered a developmental window where dysregulated GSK3β activity disrupts mitochondrial function. Notably, a partial inhibition of GSK3β activity in FXS fibroblasts from young individuals rescues the observed mitochondrial defects, suggesting that targeting GSK3β in the early stages may offer therapeutic benefits for this condition.

Abstract Image

查看原文本刊更多论文

GSK3β 的早期失调会损害脆性 X 综合征的线粒体活性。

线粒体活动的精细调节对大脑的正常发育至关重要。脆性 X 综合征（FXS）是导致遗传性智力障碍的主要原因，它是一种神经发育障碍性疾病，线粒体功能障碍已被越来越多地牵涉其中。本研究调查了糖原合成酶激酶 3β（GSK3β）在 FXS 中的作用。已有多项研究报道了 GSK3β 在 FXS 中的失调，其在线粒体功能中的作用也已为人所知。然而，FXS 中 GSK3β 活性紊乱与线粒体功能障碍之间的联系仍有待探索。利用 Fmr1 基因敲除（KO）小鼠和来自 FXS 患者的人类细胞系，我们发现了 GSK3β 活性失调破坏线粒体功能的发育窗口期。值得注意的是，部分抑制来自年轻个体的FXS成纤维细胞中GSK3β的活性可以挽救观察到的线粒体缺陷，这表明在早期阶段以GSK3β为靶点可能对这种疾病有治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Neurobiology of Disease 医学-神经科学

CiteScore

11.20

自引率

3.30%

发文量

270

审稿时长

76 days

期刊介绍： Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.