Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits.
Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits.
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DOI：
10.1126/science.aaa9344
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发表时间：
2015-06-05
期刊：
影响因子：
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通讯作者：
Petrucelli L
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文献类型：
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作者：
Chew J;Gendron TF;Prudencio M;Sasaguri H;Zhang YJ;Castanedes-Casey M;Lee CW;Jansen-West K;Kurti A;Murray ME;Bieniek KF;Bauer PO;Whitelaw EC;Rousseau L;Stankowski JN;Stetler C;Daughrity LM;Perkerson EA;Desaro P;Johnston A;Overstreet K;Edbauer D;Rademakers R;Boylan KB;Dickson DW;Fryer JD;Petrucelli L
额颞叶痴呆和肌萎缩侧索硬化的主要遗传原因是C9 ORF 72中的G4 C2重复扩增。对抗与“c9 FTD/ALS”相关的神经变性的努力受到缺乏再现疾病特征的动物模型的阻碍。我们开发了一种小鼠模型来模拟神经病理学和临床c9 FTD/ALS表型。我们通过腺相关病毒介导的体细胞脑转基因在整个小鼠中枢神经系统中表达（G4 C2）66。6月龄小鼠的脑中含有核RNA灶，包含聚（Gly-Pro），聚（Gly-Ala）和聚（Gly-Arg）二肽重复蛋白，以及TDP-43病理。这些小鼠大脑还表现出皮质神经元和小脑浦肯野细胞丢失、星形胶质细胞增生和体重减轻。（G4 C2）66小鼠也出现了与c9 FTD/ALS患者临床症状相似的行为异常，包括多动、焦虑、反社会行为和运动缺陷。
The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with “c9FTD/ALS” are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.