Koppers Max, Blokhuis Anna M, Westeneng Henk-Jan, Terpstra Margo L, Zundel Caroline A C, Vieira de Sá Renata, Schellevis Raymond D, Waite Adrian J, Blake Derek J, Veldink Jan H, van den Berg Leonard H, Pasterkamp R Jeroen
Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
Ann Neurol. 2015 Sep;78(3):426-38. doi: 10.1002/ana.24453. Epub 2015 Jul 3.
How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain- and loss-of-function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect of C9orf72 loss-of-function in mice.
We generated and analyzed a conditional C9orf72 knockout mouse model. C9orf72(fl/fl) mice were crossed with Nestin-Cre mice to selectively remove C9orf72 from neurons and glial cells. Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP-43 mislocalization. In addition, motor function and survival were assessed.
Neural-specific ablation of C9orf72 in conditional C9orf72 knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival.
Our data suggest that C9orf72 loss-of-function, by itself, is insufficient to cause motor neuron disease. These results may have important implications for the development of therapeutic strategies for C9orf72-associated ALS.
C9ORF72基因中的六核苷酸（GGGGCC）重复扩增如何导致肌萎缩侧索硬化症（ALS）仍知之甚少。功能获得和功能丧失机制均有提出。然而，体内支持这些机制的证据并不完整。在此，我们确定了C9orf72功能丧失在小鼠中的影响。
我们构建并分析了一个条件性C9orf72基因敲除小鼠模型。将C9orf72(fl/fl)小鼠与Nestin-Cre小鼠杂交，以选择性地从神经元和神经胶质细胞中去除C9orf72。进行免疫组织化学研究运动神经元和神经肌肉完整性，以及ALS的几种病理特征，如胶质增生和TDP-43错误定位。此外，评估运动功能和生存期。
条件性C9orf72基因敲除小鼠中C9orf72的神经特异性缺失导致体重显著减轻，但未诱导运动神经元变性、运动功能缺陷或生存期改变。
我们的数据表明，C9orf72功能丧失本身不足以导致运动神经元疾病。这些结果可能对C9orf72相关ALS治疗策略的开发具有重要意义。
