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Gene Expression Analysis Exposes Mitochondrial Abnormalities in a Mouse Model of Rett Syndrome

机译:基因表达分析揭示Rett综合征的小鼠模型中的线粒体异常。

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Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked MECP2 gene, which encodes a methyl-CpG binding transcriptional repressor. Using the Mecp2-null mouse (an animal model for RTT) and differential display, we found that mice with neurological symptoms overexpress the nuclear gene for ubiquinol-cytochrome c reductase core protein 1 (Uqcrc1). Chromatin immunoprecipitation demonstrated that MeCP2 interacts with the Uqcrc1 promoter. Uqcrc1 encodes a subunit of mitochondrial respiratory complex III, and isolated mitochondria from the Mecp2-null brain showed elevated respiration rates associated with respiratory complex III and an overall reduction in coupling. A causal link between Uqcrc1 gene overexpression and enhanced complex III activity was established in neuroblastoma cells. Our findings raise the possibility that mitochondrial dysfunction contributes to pathology of the Mecp2-null mouse and may contribute to the long-known resemblance between Rett syndrome and certain mitochondrial disorders.
机译:Rett综合征(RTT)是一种严重的神经系统疾病,由X链接的 MECP2 基因突变引起,该基因编码甲基CpG结合转录阻遏物。使用 Mecp2 -null小鼠(RTT的动物模型)和差异展示,我们发现具有神经系统症状的小鼠过表达泛醇-细胞色素 c 还原酶核心蛋白的核基因1( Uqcrc1 )。染色质的免疫沉淀表明MeCP2与 Uqcrc1 启动子相互作用。 Uqcrc1 编码线粒体呼吸复合物III的一个亚基,从 Mecp2 无脑的分离的线粒体显示出与呼吸复合物III相关的呼吸速率升高,并且耦合降低。在神经母细胞瘤细胞中建立了 Uqcrc1 基因过表达与复合物III活性增强之间的因果关系。我们的发现增加了线粒体功能障碍导致 Mecp2 -null小鼠病理的可能性,并可能导致了Rett综合征与某些线粒体疾病之间的长期相似性。

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