Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models.

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-10-14 DOI:10.1038/s44321-024-00151-w
Alessandro Esposito,Tommaso Seri,Martina Breccia,Marzia Indrigo,Giuseppina De Rocco,Francesca Nuzzolillo,Vanna Denti,Francesca Pappacena,Gaia Tartaglione,Simone Serrao,Giuseppe Paglia,Luca Murru,Stefano de Pretis,Jean-Michel Cioni,Nicoletta Landsberger,Fabrizia Claudia Guarnieri,Michela Palmieri
{"title":"Unraveling autophagic imbalances and therapeutic insights in Mecp2-deficient models.","authors":"Alessandro Esposito,Tommaso Seri,Martina Breccia,Marzia Indrigo,Giuseppina De Rocco,Francesca Nuzzolillo,Vanna Denti,Francesca Pappacena,Gaia Tartaglione,Simone Serrao,Giuseppe Paglia,Luca Murru,Stefano de Pretis,Jean-Michel Cioni,Nicoletta Landsberger,Fabrizia Claudia Guarnieri,Michela Palmieri","doi":"10.1038/s44321-024-00151-w","DOIUrl":null,"url":null,"abstract":"Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles.Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B, probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s44321-024-00151-w","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Loss-of-function mutations in MECP2 are associated to Rett syndrome (RTT), a severe neurodevelopmental disease. Mainly working as a transcriptional regulator, MeCP2 absence leads to gene expression perturbations resulting in deficits of synaptic function and neuronal activity. In addition, RTT patients and mouse models suffer from a complex metabolic syndrome, suggesting that related cellular pathways might contribute to neuropathogenesis. Along this line, autophagy is critical in sustaining developing neuron homeostasis by breaking down dysfunctional proteins, lipids, and organelles.Here, we investigated the autophagic pathway in RTT and found reduced content of autophagic vacuoles in Mecp2 knock-out neurons. This correlates with defective lipidation of LC3B, probably caused by a deficiency of the autophagic membrane lipid phosphatidylethanolamine. The administration of the autophagy inducer trehalose recovers LC3B lipidation, autophagosomes content in knock-out neurons, and ameliorates their morphology, neuronal activity and synaptic ultrastructure. Moreover, we provide evidence for attenuation of motor and exploratory impairment in Mecp2 knock-out mice upon trehalose administration. Overall, our findings open new perspectives for neurodevelopmental disorders therapies based on the concept of autophagy modulation.
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
揭示 Mecp2 缺陷模型的自噬失衡和治疗启示
MECP2功能缺失突变与严重神经发育疾病雷特综合征(RTT)有关。MeCP2 主要起转录调节作用,其缺失会导致基因表达紊乱,造成突触功能和神经元活动的缺陷。此外,RTT 患者和小鼠模型还患有复杂的代谢综合征,这表明相关的细胞通路可能会导致神经发病。沿着这一思路,自噬在通过分解功能失调的蛋白质、脂质和细胞器来维持发育中神经元的稳态方面起着至关重要的作用。这与LC3B的脂化缺陷有关,可能是自噬膜脂质磷脂酰乙醇胺缺乏所致。给予自噬诱导剂曲哈洛糖可恢复基因敲除神经元的 LC3B 脂化和自噬体含量,并改善其形态、神经元活动和突触超微结构。此外,我们还提供了证据,证明给予曲哈洛糖可减轻 Mecp2 基因敲除小鼠的运动和探索障碍。总之,我们的发现为基于自噬调节概念的神经发育障碍疗法开辟了新的前景。
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 去求助
来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
期刊最新文献
Rett syndrome: interferon-γ to the rescue? A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import. Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects. Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47. Targeting USP11 regulation by a novel lithium-organic coordination compound improves neuropathologies and cognitive functions in Alzheimer transgenic mice.
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1