Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
PLoS Genet. 2011 Jun;7(6):e1002102. doi: 10.1371/journal.pgen.1002102. Epub 2011 Jun 2.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in Fragile X premutation carriers. Previous studies found that Fragile X rCGG repeats are sufficient to cause neurodegeneration and that the rCGG repeat-binding proteins Pur α and hnRNP A2/B1 can modulate rCGG-mediated neuronal toxicity. To explore the role of Pur α in rCGG-mediated neurodegeneration further, we took a proteomic approach and identified more than 100 proteins that interact with Pur α. Of particular interest is Rm62, the Drosophila ortholog of p68 RNA helicase, which could modulate rCGG-mediated neurodegeneration. Here we show that rCGG repeats decreased the expression of Rm62 posttranscriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional mRNAs involved in stress and immune responses. Together these findings suggest that abnormal nuclear accumulation of these mRNAs, likely as a result of impaired nuclear export, could contribute to FXTAS pathogenesis.
脆性 X 相关震颤/共济失调综合征（FXTAS）是脆性 X 前突变携带者中出现的神经退行性疾病。先前的研究发现，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 Pur α 和 hnRNP A2/B1 可以调节 rCGG 介导的神经元毒性。为了进一步探讨 Pur α 在 rCGG 介导的神经退行性变中的作用，我们采用蛋白质组学方法鉴定了 100 多种与 Pur α 相互作用的蛋白质。特别有趣的是 Rm62，它是果蝇中 p68 RNA 解旋酶的同源物，它可以调节 rCGG 介导的神经退行性变。在这里，我们发现 rCGG 重复序列在后转录水平降低了 Rm62 的表达，导致 Hsp70 转录本以及参与应激和免疫反应的其他 mRNA 在核内积累。这些发现表明，这些 mRNA 的异常核内积累，可能是由于核输出受损，可能导致 FXTAS 的发病机制。
