O'Rourke Jacqueline G, Bogdanik Laurent, Muhammad A K M G, Gendron Tania F, Kim Kevin J, Austin Andrew, Cady Janet, Liu Elaine Y, Zarrow Jonah, Grant Sharday, Ho Ritchie, Bell Shaughn, Carmona Sharon, Simpkinson Megan, Lall Deepti, Wu Kathryn, Daughrity Lillian, Dickson Dennis W, Harms Matthew B, Petrucelli Leonard, Lee Edward B, Lutz Cathleen M, Baloh Robert H
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Neuron. 2015 Dec 2;88(5):892-901. doi: 10.1016/j.neuron.2015.10.027.
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 (∼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.
C9orf72基因中六核苷酸重复序列（GGGGCC）的非编码扩增是家族性肌萎缩侧索硬化症和额颞叶痴呆最常见的病因。在此，我们报告了携带细菌人工染色体（BAC）的转基因小鼠，该BAC包含具有正常等位基因（15次重复）或疾病相关扩增（约100 - 1000次重复；C9 - BACexp）的完整人类C9orf72基因。C9 - BACexp小鼠表现出C9orf72扩增患者中所见的病理特征，包括广泛的RNA病灶和重复相关的非ATG（RAN）翻译二肽，这些被靶向人类C9orf72的反义寡核苷酸所抑制。核仁素分布发生改变，支持C9orf72转录本或RAN二肽促进核仁功能障碍的观点。尽管C9 - BACexp小鼠早期就广泛产生RNA病灶和RAN二肽，但即使在老年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二肽在症状前出现且在小鼠中不足以像在患者中那样引发神经退行性变的假说。
