Department of Neurobiology and Genetics, IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France.
EMBO J. 2010 Apr 7;29(7):1248-61. doi: 10.1038/emboj.2010.21. Epub 2010 Feb 25.
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by expansion of 55-200 CGG repeats in the 5'-UTR of the FMR1 gene. FXTAS is characterized by action tremor, gait ataxia and impaired executive cognitive functioning. It has been proposed that FXTAS is caused by titration of RNA-binding proteins by the expanded CGG repeats. Sam68 is an RNA-binding protein involved in alternative splicing regulation and its ablation in mouse leads to motor coordination defects. Here, we report that mRNAs containing expanded CGG repeats form large and dynamic intranuclear RNA aggregates that recruit several RNA-binding proteins sequentially, first Sam68, then hnRNP-G and MBNL1. Importantly, Sam68 is sequestered by expanded CGG repeats and thereby loses its splicing-regulatory function. Consequently, Sam68-responsive splicing is altered in FXTAS patients. Finally, we found that regulation of Sam68 tyrosine phosphorylation modulates its localization within CGG aggregates and that tautomycin prevents both Sam68 and CGG RNA aggregate formation. Overall, these data support an RNA gain-of-function mechanism for FXTAS neuropathology, and suggest possible target routes for treatment options.
脆性 X 相关震颤共济失调综合征（FXTAS）是一种神经退行性疾病，由 FMR1 基因 5'UTR 中的 55-200 个 CGG 重复扩展引起。FXTAS 的特征是动作震颤、步态共济失调和执行认知功能受损。有人提出，FXTAS 是由扩展的 CGG 重复滴定 RNA 结合蛋白引起的。Sam68 是一种参与可变剪接调节的 RNA 结合蛋白，其在小鼠中的缺失导致运动协调缺陷。在这里，我们报告说含有扩展 CGG 重复的 mRNA 形成大的和动态的核内 RNA 聚集体，这些聚集体依次招募几个 RNA 结合蛋白，首先是 Sam68，然后是 hnRNP-G 和 MBNL1。重要的是，Sam68 被扩展的 CGG 重复所隔离，从而失去其剪接调节功能。因此，Sam68 反应性剪接在 FXTAS 患者中发生改变。最后，我们发现 Sam68 酪氨酸磷酸化的调节调节其在 CGG 聚集体中的定位，并且 tautomycin 可以防止 Sam68 和 CGG RNA 聚集体的形成。总的来说，这些数据支持 FXTAS 神经病理学的 RNA 获得性功能机制，并为治疗选择提供了可能的靶向途径。
