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.

中文翻译：

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人源化突变体FUS在'FUSDelta14'敲入小鼠中驱动进行性运动神经元变性而无聚集

FUS突变是导致肌萎缩性侧索硬化症的主要遗传方式。试图在小鼠中模拟FUS肌萎缩性侧索硬化症（ALS）时，很明显FUS具有剂量敏感性，其作用本身是由过表达引起的在转基因菌株中。需要新的模型来维持FUS表达的生理水平并概括人类疾病-随着杂合动物中运动神经元的逐渐丧失。在这里，我们描述了一种具有移码突变的新型人源化FUS-ALS小鼠，它符合两个标准：FUS Delta14小鼠。杂合动物在生理水平上表达突变的人源化FUS蛋白，并具有成年发作的进行性运动神经元丢失和神经肌肉接头失神经。此外，我们产生了针对独特的人类移码肽表位的新型抗体，仅能特异性鉴定突变型FUS。使用我们的新FUSDelta14 ALS小鼠抗体系统，我们显示了神经变性在FUS蛋白不存在的情况下发生。随着疾病的进展，FUS的错误定位增加了，突变的FUS聚集在粗糙的内质网上。此外，转录组分析显示，随着疾病的早期发展，核糖体蛋白水平和线粒体功能的进行性变化。因此，我们的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。