The hexanucleotide G₄C₂ repeat expansion in the first intron of the C9ORF72 gene explains the majority of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) cases. Numerous studies have indicated the toxicity of dipeptide repeats (DPRs) which are produced via repeat-associated non-AUG (RAN) translation from the repeat expansion and accumulate in the brain of C9FTD/ALS patients. Mouse models expressing the human C9ORF72 repeat and/or DPRs show variable pathological, functional, and behavioral characteristics of FTD and ALS. Here, we report a new Tet-on inducible mouse model that expresses 36x pure G₄C₂ repeats with 100bp upstream and downstream human flanking regions. Brain specific expression causes the formation of sporadic sense DPRs aggregates upon 6 months dox induction but no apparent neurodegeneration. Expression in the rest of the body evokes abundant sense DPRs in multiple organs, leading to weight loss, neuromuscular junction disruption, myopathy, and a locomotor phenotype within the time frame of four weeks. We did not observe any RNA foci or pTDP-43 pathology. Accumulation of DPRs and the myopathy phenotype could be prevented when 36x G₄C₂ repeat expression was stopped after 1 week. After 2 weeks of expression, the phenotype could not be reversed, even though DPR levels were reduced. In conclusion, expression of 36x pure G₄C₂ repeats including 100bp human flanking regions is sufficient for RAN translation of sense DPRs and evokes a functional locomotor phenotype. Our inducible mouse model suggests early diagnosis and treatment are important for C9FTD/ALS patients.

中文翻译：

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人C9ORF72 36x G4C2六核苷酸重复序列的诱导表达足以引起RAN翻译和小鼠快速肌肉萎缩。

C9ORF72基因的第一个内含子中的六核苷酸G ₄ C ₂重复扩增解释了大多数额颞叶痴呆（FTD）和肌萎缩性侧索硬化症（ALS）病例。大量研究表明，二肽重复序列（DPR）的毒性是通过重复序列扩展中的重复相关非AUG（RAN）翻译产生的，并在C9FTD / ALS患者的大脑中积累。表达人类C9ORF72重复序列和/或DPR的小鼠模型显示了FTD和ALS的可变病理，功能和行为特征。在这里，我们报告一个新的Tet-on诱导型小鼠模型，该模型表达36倍纯G ₄ C ₂以100bp上游和下游人类侧翼区域重复。脑特异性表达导致6个月dox诱导后散发有义DPR聚集，但无明显的神经退行性变。在身体其余部位的表达会在多个器官中引起丰富的DPR，从而导致体重减轻，神经肌肉连接破坏，肌病和四周内的运动表型。我们没有观察到任何RNA病灶或pTDP-43病理。1周后停止36x G ₄ C ₂重复表达时，可以防止DPR的积累和肌病表型。表达2周后，即使DPR水平降低，该表型也无法逆转。总之，表达了36个纯G ₄ C ₂包括100bp人侧翼区的重复序列足以进行有义DPR的RAN翻译，并引起功能性自发表型。我们的诱导小鼠模型表明，早期诊断和治疗对C9FTD / ALS患者很重要。