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首页> 外文期刊>Neuron >C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD
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C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

机译：C9orf72 BAC转基因小鼠显示ALS / FTD的典型病理特征

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摘要

Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (similar to 100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.
机译：C9orf72基因中六核苷酸重复序列（GGGGCC）的非编码扩展是家族性肌萎缩性侧索硬化症和额颞痴呆的最常见原因。在这里，我们报告转基因小鼠携带细菌人工染色体（BAC），其中包含完整的人C9orf72基因以及正常等位基因（15个重复）或与疾病相关的扩增（类似于100-1,000个重复; C9-BACexp）。 C9-BACexp小鼠显示出在C9orf72扩增患者中看到的病理特征，包括广泛的RNA病灶和重复相关的非ATG（RAN）翻译的二肽，这些抗原被靶向人C9orf72的反义寡核苷酸所抑制。核仁蛋白的分布发生变化，支持C9orf72转录本或RAN二肽促进核仁功能障碍。尽管在C9-BACexp小鼠中早期广泛产生RNA病灶和RAN二肽，但即使在高龄时也未观察到行为异常和神经退行性变，这支持了RNA病灶和RAN二肽在症状发生前发生并且不足以促使小鼠神经退行性变的假说。患者中看到的水平。

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