KCNT1(Slack)钾通道功能缺失或增益小鼠模型的分子谱分析及反义寡核苷酸治疗。

IF 4.8 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Biomolecules Pub Date : 2024-11-02 DOI:10.3390/biom14111397
Fangxu Sun, Huafeng Wang, Jing Wu, Imran H Quraishi, Yalan Zhang, Maysam Pedram, Benbo Gao, Elizabeth A Jonas, Viet Nguyen, Sijia Wu, Omar S Mabrouk, Paymaan Jafar-Nejad, Leonard K Kaczmarek
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引用次数: 0

摘要

钾钠激活通道亚型 T 成员 1(KCNT1)基因编码 Slack 通道 KNa1.1,该通道在整个大脑的神经元中都有表达。KCNT1 的功能增益变异与一系列癫痫综合征有关,携带这些变异的小鼠表现出与患者相似的强健表型。然而,Kcnt1基因敲除(KO)小鼠寿命正常,却没有任何癫痫表型。为了了解这两种模型之间的分子差异,我们对 Kcnt1 KO 和 Kcnt1R455H/+ 小鼠的大脑皮层进行了全面的蛋白质组学分析,Kcnt1R455H/+ 小鼠是一种细胞质 C 端突变的动物模型,与导致 EIMFS 的人类 R474H 变体同源。与野生型小鼠相比,在 Kcnt1 KO 小鼠中观察到的最大变化是线粒体内膜多种蛋白质的表达量增加。对 Kcnt1 KO 小鼠皮质线粒体的电子显微镜研究进一步证实,与野生型小鼠相比,线粒体嵴的密度显著增加。在 Kcnt1R455H/+ 小鼠中使用小鼠特异性 Kcnt1 反义寡核苷酸 (ASO) 减少 Kcnt1,部分纠正了疾病模型中的蛋白质组失调。这些结果支持了这样的假设:ASO 介导的 KCNT1 减少可用于治疗 KCNT1 癫痫。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular Profiling of Mouse Models of Loss or Gain of Function of the KCNT1 (Slack) Potassium Channel and Antisense Oligonucleotide Treatment.

The potassium sodium-activated channel subtype T member 1 (KCNT1) gene encodes the Slack channel KNa1.1, which is expressed in neurons throughout the brain. Gain-of-function variants in KCNT1 are associated with a spectrum of epilepsy syndromes, and mice carrying those variants exhibit a robust phenotype similar to that observed in patients. Kcnt1 knockout (KO) mice, however, have a normal lifespan without any epileptic phenotype. To understand the molecular differences between these two models, we conducted a comprehensive proteomic analysis of the cerebral cortices of Kcnt1 KO and Kcnt1R455H/+ mice, an animal model bearing a cytoplasmic C-terminal mutation homologous to a human R474H variant that results in EIMFS. The greatest change observed in Kcnt1 KO mice compared to the wild-type mice was the increased expression of multiple proteins of the inner mitochondrial membrane. Electron microscopy studies of cortical mitochondria from Kcnt1 KO mice further confirmed a significant increase in the density of mitochondrial cristae compared to that in wild-type mice. Kcnt1 reduction by a murine-specific Kcnt1 antisense oligonucleotide (ASO) in Kcnt1R455H/+ mice partially corrected the proteomic dysregulations in the disease model. The results support the hypothesis that ASO-mediated KCNT1 reduction could be therapeutically useful in the treatment of KCNT1 epilepsies.

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来源期刊
Biomolecules
Biomolecules Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
3.60%
发文量
1640
审稿时长
18.28 days
期刊介绍: Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications.  Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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