交替偏瘫的儿童相关突变的Atp1a3揭示了不同的神经改变小鼠。

IF 5.6 2区 医学 Q1 NEUROSCIENCES
Markus Terrey , Georgii Krivoshein , Scott I. Adamson , Elena Arystarkhova , Laura Anderson , John Szwec , Shelby McKee , Holly Jones , Sara Perkins , Vijay Selvam , Pierre-Alexandre Piec , Dweet Chhaya , Ari Dehn , Aamir Zuberi , Stephen A. Murray , Natalia S. Morsci , Kathleen J. Sweadner , David A. Knowles , Else A. Tolner , Arn M.J.M. van den Maagdenberg , Cathleen M. Lutz
{"title":"交替偏瘫的儿童相关突变的Atp1a3揭示了不同的神经改变小鼠。","authors":"Markus Terrey ,&nbsp;Georgii Krivoshein ,&nbsp;Scott I. Adamson ,&nbsp;Elena Arystarkhova ,&nbsp;Laura Anderson ,&nbsp;John Szwec ,&nbsp;Shelby McKee ,&nbsp;Holly Jones ,&nbsp;Sara Perkins ,&nbsp;Vijay Selvam ,&nbsp;Pierre-Alexandre Piec ,&nbsp;Dweet Chhaya ,&nbsp;Ari Dehn ,&nbsp;Aamir Zuberi ,&nbsp;Stephen A. Murray ,&nbsp;Natalia S. Morsci ,&nbsp;Kathleen J. Sweadner ,&nbsp;David A. Knowles ,&nbsp;Else A. Tolner ,&nbsp;Arn M.J.M. van den Maagdenberg ,&nbsp;Cathleen M. Lutz","doi":"10.1016/j.nbd.2025.106954","DOIUrl":null,"url":null,"abstract":"<div><div>Pathogenic variants in the neuronal Na<sup>+</sup>/K<sup>+</sup> ATPase transmembrane ion transporter (<em>ATP1A3</em>) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common <em>de novo</em> pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the <em>Atp1a3</em> gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106954"},"PeriodicalIF":5.6000,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice\",\"authors\":\"Markus Terrey ,&nbsp;Georgii Krivoshein ,&nbsp;Scott I. Adamson ,&nbsp;Elena Arystarkhova ,&nbsp;Laura Anderson ,&nbsp;John Szwec ,&nbsp;Shelby McKee ,&nbsp;Holly Jones ,&nbsp;Sara Perkins ,&nbsp;Vijay Selvam ,&nbsp;Pierre-Alexandre Piec ,&nbsp;Dweet Chhaya ,&nbsp;Ari Dehn ,&nbsp;Aamir Zuberi ,&nbsp;Stephen A. Murray ,&nbsp;Natalia S. Morsci ,&nbsp;Kathleen J. Sweadner ,&nbsp;David A. Knowles ,&nbsp;Else A. Tolner ,&nbsp;Arn M.J.M. van den Maagdenberg ,&nbsp;Cathleen M. Lutz\",\"doi\":\"10.1016/j.nbd.2025.106954\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Pathogenic variants in the neuronal Na<sup>+</sup>/K<sup>+</sup> ATPase transmembrane ion transporter (<em>ATP1A3</em>) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common <em>de novo</em> pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the <em>Atp1a3</em> gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.</div></div>\",\"PeriodicalId\":19097,\"journal\":{\"name\":\"Neurobiology of Disease\",\"volume\":\"212 \",\"pages\":\"Article 106954\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-05-15\",\"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/S0969996125001706\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurobiology of Disease","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0969996125001706","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

摘要

神经元Na+/K+ atp酶跨膜离子转运体(ATP1A3)的致病性变异引起一系列神经系统疾病,包括儿童交替偏瘫(AHC)。在AHC中最常见的新发致病变异是p.D801N(约40% %的患者)和p.d 815k(约25% %的患者),这两种变异可导致小鼠因自发死亡而早期死亡。然而,没有过早死亡障碍的临床相关神经表型发展的知识对于确定病理生理机制以及最终在疾病模型中测试治疗策略至关重要。在这里,我们使用杂交活力试图减轻AHC小鼠的脆弱性,然后进行行为、电生理、生化和分子测试,比较分析携带两种最常见AHC患者观察到的Atp1a3基因变异的小鼠。总的来说,我们的数据揭示了p.D801N和p.E815K变异对疾病相关改变(如自发性和应激性发作、运动功能、行为和神经生理活动以及神经炎症)的存在和差异影响。我们的替代AHC小鼠模型及其表型缺陷为ATP1A3研究的疾病生物学研究和治疗测试开辟了新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice
Pathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.
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
Neurobiology of Disease
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.
×
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