Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity.

中文翻译：

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C9ORF72 功能降低会加剧 ALS/FTD 毒性的增加，导致 C9orf72 中的重复扩增。

编码预测的鸟嘌呤交换因子的 C9orf72 中的六核苷酸扩增是肌萎缩侧索硬化 (ALS) 和额颞叶痴呆 (FTD) 最常见的遗传原因。尽管已经建立重复扩增以产生有毒产物，但编码 C9ORF72 蛋白的 mRNA 在受影响的个体中也减少了。在这项研究中，我们测试了 C9ORF72 蛋白水平如何影响重复介导的毒性。在表达 66 个 GGGGCC 重复序列的体细胞转基因小鼠中，一个或两个内源性 C9orf72 等位基因的失活分别引发或加速了早期死亡。在表达具有 450 个不编码 C9ORF72 蛋白的重复 C9orf72 转基因的小鼠中，一个或两个内源性 C9orf72 等位基因的失活加剧了认知缺陷、海马神经元丢失、通过翻译含重复的 RNA 来激活和积累二肽重复蛋白。显示减少的 C9ORF72 可抑制重复介导的自噬升高。这些努力支持了由 C9ORF72 减少导致的 ALS/FTD 疾病机制，这可能导致自噬缺陷，与重复依赖的毒性增益协同作用。