Division of Histology and Embryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China.
Hum Mol Genet. 2012 Jan 1;21(1):57-65. doi: 10.1093/hmg/ddr437. Epub 2011 Sep 22.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with fragile X premutation carriers. Previous studies have shown that fragile X rCGG repeats are sufficient to cause neurodegeneration and that the rCGG-repeat-binding proteins Pur α and heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 could modulate rCGG-mediated neuronal toxicity. Mobile genetic elements or their remnants populate the genomes, and the activities of these elements are tightly controlled for the fitness of host genomes in different organisms. Here we provide both biochemical and genetic evidence to show that the activation of a specific retrotransposon, gypsy, can modulate rCGG-mediated neurodegeneration in an FXTAS Drosophila model. We find that one of the rCGG-repeat-binding proteins, hnRNP A2/B1, is involved in this process via interaction with heterochromatin protein 1. Knockdown of gypsy RNA by RNAi could suppress the neuronal toxicity caused by rCGG repeats. These data together point to a surprisingly active role for retrotransposition in neurodegeneration.
脆性 X 相关震颤共济失调综合征（FXTAS）是一种与脆性 X 前突变携带者相关的神经退行性疾病。先前的研究表明，脆性 X rCGG 重复序列足以引起神经退行性变，并且 rCGG 重复序列结合蛋白 Purα 和异质核核糖核蛋白（hnRNP）A2/B1 可以调节 rCGG 介导的神经元毒性。移动遗传元件或其残余物存在于基因组中，这些元件的活性在不同生物体的宿主基因组中受到严格控制，以适应其生存需要。在这里，我们提供了生化和遗传证据，表明特定的逆转录转座子 gypsy 的激活可以在 FXTAS 果蝇模型中调节 rCGG 介导的神经退行性变。我们发现，rCGG 重复序列结合蛋白之一 hnRNP A2/B1 通过与异染色质蛋白 1 的相互作用参与了这一过程。通过 RNAi 敲低 gypsy RNA 可以抑制 rCGG 重复序列引起的神经元毒性。这些数据共同指出逆转座在神经退行性变中起着出人意料的活跃作用。
