小鼠的显性阴性 Kcnd3 F227del 突变会损害 ER 和高尔基体的功能,从而导致脊髓小脑共济失调 22 型(SCA22)。

IF 5.6 2区 医学 Q1 ONCOLOGY
Hao-Chih Hung, Jia-Han Lin, Yuan-Chi Teng, Cheng-Heng Kao, Pei-Yu Wang, Bing-Wen Soong, Ting-Fen Tsai
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引用次数: 0

摘要

由 KCND3 突变引起的脊髓小脑共济失调 22 型(SCA22)是一种常染色体显性遗传疾病。我们建立了一个携带 Kcnd3 F227del 突变的小鼠模型,以研究其分子发病机制。我们得出了四项发现。首先,杂合子小鼠在运动协调和平衡方面表现出与 SCA22 患者相同的早期发病缺陷。Purkinje细胞的退化和轻微缺失,加上同时存在的神经炎症,以及之前的电生理变化发现,都可能导致携带Kcnd3 F227del突变蛋白的小鼠出现SCA22共济失调表型。其次,突变体蛋白被内质网和高尔基体截留,导致未折叠蛋白反应的激活和严重的转运缺陷,从而影响其膜的去向。耐人寻味的是,高尔基体的严重破坏是最早的表现形式。第三,转录组分析表明,Kcnd3 F227del 突变下调了一系列涉及突触功能和神经发生的基因,而突触和神经发生与浦肯野细胞的功能密切相关。最后,在携带 Kcnd3 功能缺失突变的基因敲除小鼠中检测不到共济失调表型。因此,Kcnd3 F227del 是一种显性阴性突变。该小鼠模型可作为临床前模型,用于探索治疗患者的策略。© 2024 作者。病理学杂志》由约翰威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A dominant negative Kcnd3 F227del mutation in mice causes spinocerebellar ataxia type 22 (SCA22) by impairing ER and Golgi functioning

A dominant negative Kcnd3 F227del mutation in mice causes spinocerebellar ataxia type 22 (SCA22) by impairing ER and Golgi functioning

Spinocerebellar ataxia type 22 (SCA22) caused by KCND3 mutations is an autosomal dominant disorder. We established a mouse model carrying the Kcnd3 F227del mutation to study the molecular pathogenesis. Four findings were pinpointed. First, the heterozygous mice exhibited an early onset of defects in motor coordination and balance which mirror those of SCA22 patients. The degeneration and a minor loss of Purkinje cells, together with the concurrent presence of neuroinflammation, as well as the previous finding on electrophysiological changes, may all contribute to the development of the SCA22 ataxia phenotype in mice carrying the Kcnd3 F227del mutant protein. Second, the mutant protein is retained by the endoplasmic reticulum and Golgi, leading to activation of the unfolded protein response and a severe trafficking defect that affects its membrane destination. Intriguingly, profound damage of the Golgi is the earliest manifestation. Third, analysis of the transcriptome revealed that the Kcnd3 F227del mutation down-regulates a panel of genes involved in the functioning of synapses and neurogenesis which are tightly linked to the functioning of Purkinje cells. Finally, no ataxia phenotypes were detectable in knockout mice carrying a loss-of-function Kcnd3 mutation. Thus, Kcnd3 F227del is a dominant-negative mutation. This mouse model may serve as a preclinical model for exploring therapeutic strategies to treat patients. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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来源期刊
The Journal of Pathology
The Journal of Pathology 医学-病理学
CiteScore
14.10
自引率
1.40%
发文量
144
审稿时长
3-8 weeks
期刊介绍: The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.
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