小柯机器人

C9ORF72功能降低会加剧肌萎缩性侧索硬化症（ALS）/额颞痴呆（FTD）的毒性，导致C9orf72（编码预测的鸟嘌呤交换因子）重复扩增。这一成果由加州大学圣地亚哥分校Don W. Cleveland和哈佛医学院Clotilde Lagier-Tourenne团队合作取得，并发表在2020年4月13日出版的《自然-神经科学》杂志上。

在这项研究中，研究人员检测了C9ORF72蛋白水平如何影响重复介导的毒性。在体细胞表达66个GGGGCC重复序列的转基因小鼠中，内源性C9orf72等位基因的一个或两个失活分别引起或加速早期死亡。

在表达带有450个不编码C9ORF72重复序列的C9orf72转基因小鼠中，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、神经胶质细胞的活化和二肽重复蛋白的积累（来自含重复序列RNA的翻译）。C9ORF72的减少可抑制自噬过程中重复介导的升高。这些数据支持了由C9ORF72减少导致的ALS / FTD致病机制，这可能导致自噬缺陷并与重复依赖的毒性增加协同作用。

据悉，编码一种预测的鸟嘌呤交换因子的C9orf72中六核苷酸扩增是肌萎缩性侧索硬化症和额颞痴呆中最常见遗传原因。尽管已经确定重复扩增可产生有毒产物，但在受影响的个体中编码C9ORF72蛋白的mRNA也减少了。

附：英文原文

Title: Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72

Author: Qiang Zhu, Jie Jiang, Tania F. Gendron, Melissa McAlonis-Downes, Lulin Jiang, Amy Taylor, Sandra Diaz Garcia, Somasish Ghosh Dastidar, Maria J. Rodriguez, Patrick King, Yongjie Zhang, Albert R. La Spada, Huaxi Xu, Leonard Petrucelli, John Ravits, Sandrine Da Cruz, Clotilde Lagier-Tourenne, Don W. Cleveland

Issue&Volume: 2020-04-13

Abstract: 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.

DOI: 10.1038/s41593-020-0619-5

Source: https://www.nature.com/articles/s41593-020-0619-5

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex