Peters Owen M, Cabrera Gabriela Toro, Tran Helene, Gendron Tania F, McKeon Jeanne E, Metterville Jake, Weiss Alexandra, Wightman Nicholas, Salameh Johnny, Kim Juyhun, Sun Huaming, Boylan Kevin B, Dickson Dennis, Kennedy Zack, Lin Ziqiang, Zhang Yong-Jie, Daughrity Lillian, Jung Chris, Gao Fen-Biao, Sapp Peter C, Horvitz H Robert, Bosco Daryl A, Brown Solange P, de Jong Pieter, Petrucelli Leonard, Mueller Chris, Brown Robert H
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Department of Pediatrics and Gene Therapy Center University of Massachusetts Medical School, Worcester, MA 01655, USA.
Neuron. 2015 Dec 2;88(5):902-909. doi: 10.1016/j.neuron.2015.11.018.
A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.
C9ORF72基因中的非编码六核苷酸重复扩增是与家族性肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）相关的最常见突变。为了研究C9ORF72在这些疾病中的病理作用，我们构建了一系列小鼠，其携带一个细菌人工染色体，该染色体包含人C9ORF72基因的外显子1至6，并带有约500个GGGGCC基序重复。这些小鼠没有明显的行为表型，但重现了C9ORF72 ALS/FTD独特的组织病理学特征，包括正义和反义核内RNA病灶以及聚（甘氨酸 - 脯氨酸）二肽重复蛋白。最后，在来自C9BAC小鼠的原代皮质神经元培养物中，使用靶向人C9ORF72的人工微小RNA，我们减弱了C9BAC转基因和聚（GP）二肽的表达。C9ORF72 BAC转基因小鼠将成为研究ALS/FTD病理生物学和治疗的宝贵工具。
