Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medicine College, Chinese Academy of Medical Sciences, Beijing, China.
Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China.
FEBS J. 2021 Mar;288(5):1712-1723. doi: 10.1111/febs.15501. Epub 2020 Aug 24.
Pathogenesis of familial amyotrophic lateral sclerosis (ALS) linked to expansion of the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat that impairs C9orf72 expression. Loss of function of the C9orf72 protein is one of the three main proposed C9orf72-related ALS mechanisms. However, C9orf72 loss of function, by itself, is insufficient to cause severe phenotypes in mice. Excitotoxicity is another major disease mechanism of ALS. We speculate that loss of C9orf72 protein might cause ALS in combination with excitotoxicity. To date, the effect of C9orf72 deficiency in the background of SD rat has not been examined. To test our hypothesis, we generated a line of rat with a deletion of part of the C9orf72 gene ablating the encoded protein. These animals did not develop any ALS phenotypes; however, when they were treated with kainic acid, an excitotoxicity inducer, the rats developed motor deficits and showed loss of motor neurons (MNs), Golgi complex fragmentation, and abnormal vesicle trafficking. RNA sequencing revealed profound changes in the gene profiles that were primarily associated with neural activity. Our results demonstrated that C9orf72 ablation alone was not enough to cause ALS pathogenesis in rat; but the ablation sensitized MNs to other risk factors that synergistically caused the ALS. These results support a loss of function of C9orf72 mechanism of ALS.
家族性肌萎缩侧索硬化症（ALS）的发病机制与染色体 9 开放阅读框 72（C9orf72）六核苷酸重复扩展有关，该重复会损害 C9orf72 的表达。C9orf72 蛋白的功能丧失是提出的三种主要 C9orf72 相关 ALS 机制之一。然而，C9orf72 功能丧失本身不足以在小鼠中引起严重表型。兴奋性毒性是 ALS 的另一个主要疾病机制。我们推测，C9orf72 蛋白的丧失可能与兴奋性毒性一起导致 ALS。迄今为止，尚未检查 SD 大鼠背景下 C9orf72 缺乏的影响。为了验证我们的假设，我们生成了一条部分缺失 C9orf72 基因的大鼠系，该基因缺失了编码的蛋白。这些动物没有出现任何 ALS 表型；然而，当它们用兴奋性毒素海人酸处理时，这些大鼠出现运动缺陷，并表现出运动神经元（MNs）丧失、高尔基复合体碎片化和异常囊泡转运。RNA 测序揭示了基因谱的深刻变化，这些变化主要与神经活动有关。我们的结果表明，C9orf72 缺失本身不足以在大鼠中引起 ALS 发病机制；但缺失使 MNs 对其他协同引起 ALS 的风险因素敏感。这些结果支持 ALS 的 C9orf72 功能丧失机制。
