A novel early onset spinocerebellar ataxia 13 BAC mouse model with cerebellar atrophy, tremor, and ataxic gait.

IF 2.2 4区 农林科学 Q1 VETERINARY SCIENCES
Junxiang Yin, Jerelyn A Nick, Swati Khare, Heidi E Kloefkorn, Ming Gao, Michael Wu, Jennifer White, James L Resnick, Kyle D Allen, Harry S Nick, Michael F Waters
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Abstract

Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant neurological disorder caused by mutations in KCNC3. Our previous studies revealed that KCNC3 (Potassium Voltage-Gated Channel Subfamily C Member 3)mutation R423H results in an early-onset form of SCA13. Previous biological models of SCA13 include zebrafish and Drosophila but no mammalian systems. More recently, mouse models with Kcnc3 mutations presented behavioral abnormalities but without obvious pathological changes in the cerebellum, a hallmark of patients with SCA13. Here, we present a novel transgenic mouse model by bacterial artificial chromosome (BAC) recombineering to express the full-length mouse Kcnc3 expressing the R424H mutation. This BAC-R424H mice exhibited behavioral and pathological changes mimicking the clinical phenotype of the disease. The BAC-R424H mice (homologous to R423H in human) developed early onset clinical symptoms with aberrant gait, tremor, and cerebellar atrophy. Histopathological analysis of the cerebellum in BAC-R424H mice showed progressive Purkinje cell loss and thinning of the molecular cell layer. Additionally, Purkinje cells of BAC-R424H mice showed significantly lower spontaneous firing frequency with a corresponding increase in inter-spike interval compared to that of wild-type mice. Our SCA13 transgenic mice recapitulate both neuropathological and behavioral changes manifested in human SCA13 R423H patients and provide an advantageous approach to understanding the role of voltage-gated potassium channel in cerebellar morphogenesis and function. This mammalian in vivo model will lead to further understanding of the R423H allelic form of SCA13 from the molecular to the behavioral level and serve as a platform for testing potential therapeutic compounds.

一种具有小脑萎缩、震颤和共济失调步态的新型早发性脊髓小脑共济失调13 BAC小鼠模型。
脊髓小脑性共济失调13 (SCA13)是由KCNC3突变引起的常染色体显性神经系统疾病。我们之前的研究表明,KCNC3(钾电压门控通道亚家族C成员3)突变R423H可导致早发型SCA13。先前的SCA13生物学模型包括斑马鱼和果蝇,但没有哺乳动物系统。最近,Kcnc3突变的小鼠模型表现出行为异常,但小脑没有明显的病理改变,这是SCA13患者的一个标志。本研究通过细菌人工染色体(BAC)重组构建了一种新的转基因小鼠模型,表达表达R424H突变的全长小鼠Kcnc3。这种BAC-R424H小鼠表现出模仿疾病临床表型的行为和病理变化。BAC-R424H小鼠(与人类的R423H同源)出现早期临床症状,包括步态异常、震颤和小脑萎缩。BAC-R424H小鼠小脑组织病理学分析显示进行性浦肯野细胞丢失和分子细胞层变薄。与野生型小鼠相比,BAC-R424H小鼠浦肯野细胞的自发放电频率明显降低,峰间间隔相应增加。我们的sc13转基因小鼠概括了人类sc13 R423H患者的神经病理和行为变化,为理解电压门控钾通道在小脑形态发生和功能中的作用提供了有利的途径。该哺乳动物体内模型将从分子水平到行为水平进一步了解SCA13的R423H等位基因形式,并为测试潜在的治疗性化合物提供平台。
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来源期刊
Experimental Animals
Experimental Animals 生物-动物学
CiteScore
2.80
自引率
4.20%
发文量
2
审稿时长
3 months
期刊介绍: The aim of this international journal is to accelerate progress in laboratory animal experimentation and disseminate relevant information in related areas through publication of peer reviewed Original papers and Review articles. The journal covers basic to applied biomedical research centering around use of experimental animals and also covers topics related to experimental animals such as technology, management, and animal welfare.
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