Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice.
Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice.
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DOI：
10.1093/brain/awx248
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发表时间：
2017-11-01
期刊：
影响因子：
--
通讯作者：
Fisher EMC
中科院分区：
文献类型：
--
作者：
Devoy A;Kalmar B;Stewart M;Park H;Burke B;Noy SJ;Redhead Y;Humphrey J;Lo K;Jaeger J;Mejia Maza A;Sivakumar P;Bertolin C;Soraru G;Plagnol V;Greensmith L;Acevedo Arozena A;Isaacs AM;Davies B;Fratta P;Fisher EMC
Devoy等人开发了第一个完全重现人FUS-ALS的小鼠模型，其定义为具有显性遗传的运动神经元的中年发病进行性变性。在没有FUS蛋白聚集的情况下发生功能的毒性获得，涉及内质网处的核糖体和线粒体的干扰。FUS突变是肌萎缩侧索硬化症的病因，具有显性遗传模式。在试图在小鼠中建立FUS-肌萎缩性侧索硬化（ALS）模型时，很明显FUS是剂量敏感性的，并且在转基因品系中的作用是由过表达本身引起的。需要新的模型来维持FUS表达的生理水平，并重现人类疾病-杂合动物中运动神经元的进行性丧失。在这里，我们描述了一种新的人源化FUS-ALS小鼠与移码突变，它满足这两个标准：FUS Delta 14小鼠。杂合子动物在生理水平表达突变的人源化FUS蛋白，并且具有成年发作的进行性运动神经元损失和神经肌肉接头的去神经支配。此外，我们产生了一种新的抗体的独特的人类移码肽表位，允许特异性识别突变FUS只。使用我们新的FUSDelta 14 ALS小鼠抗体系统，我们表明，神经变性发生在FUS蛋白聚集的情况下。FUS错误定位随着疾病进展而增加，并且突变的FUS在粗面内质网处积累。此外，转录组学分析显示，随着疾病早期阶段的开始，核糖体蛋白水平和线粒体功能发生了渐进性变化。因此，我们新的生理小鼠模型为FUS-ALS的早期发病机制提供了新的见解。
Devoy et al. develop the first mouse model to fully recapitulate human FUS-ALS, as defined by midlife-onset progressive degeneration of motor neurons with dominant inheritance. A toxic gain of function occurs in the absence of FUS protein aggregation, involving disturbance of ribosomes and mitochondria at the endoplasmic reticulum. Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease—with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.
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影响因子：
64.8
作者：
Taylor JP;Brown RH Jr;Cleveland DW
通讯作者：
Cleveland DW
影响因子：
16.6
作者：
Sharma A;Lyashchenko AK;Lu L;Nasrabady SE;Elmaleh M;Mendelsohn M;Nemes A;Tapia JC;Mentis GZ;Shneider NA
通讯作者：
Shneider NA
DOI：
10.1083/jcb.201608022
发表时间：
2017-04-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Yasuda K;Clatterbuck-Soper SF;Jackrel ME;Shorter J;Mili S
通讯作者：
Mili S
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
3.5
作者：
Shelkovnikova TA;Robinson HK;Troakes C;Ninkina N;Buchman VL
通讯作者：
Buchman VL