Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation
Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation
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DOI：
10.1093/hmg/ddv389
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发表时间：
2015-12-15
影响因子：
3.5
通讯作者：
Zarnescu, Daniela C.
中科院分区：
文献类型：
--
作者：
Coyne, Alyssa N.;Yamada, Shizuka B.;Zarnescu, Daniela C.
RNA调节异常是肌萎缩侧索硬化症（ALS）的一个新认识的发病机制。在这里，我们确定果蝇脆性X智力低下蛋白（dFMRP）作为一个强大的遗传修饰剂的TDP-43依赖性毒性的果蝇模型ALS。我们发现，dFMRP过表达（dFMRP OE）减轻TDP-43依赖的运动缺陷和减少寿命的果蝇。TDP-43和FMRP在果蝇和人类细胞中形成复合物。在运动神经元中，TDP-43表达增加了dFMRP与应激颗粒的关联，并以变体依赖性方式与polyA结合蛋白共定位。此外，dFMRP剂量调节TDP-43溶解度和分子流动性，dFMRP的过表达导致聚集体级分中TDP-43的显著减少。多核糖体分级分离实验表明，dFMRP OE也解除了futsch mRNA，TDP-43靶mRNA，调节神经肌肉突触结构的翻译抑制。恢复futsch翻译dFMRP OE减轻Futsch依赖的形态表型在神经肌肉接头，包括突触的大小和卫星终扣的存在。我们的数据表明，dFMRP通过重塑含有RNA颗粒的TDP-43、减少聚集并恢复运动神经元中特定mRNA的翻译来发挥神经保护作用。
RNA dysregulation is a newly recognized disease mechanism in amyotrophic lateral sclerosis (ALS). Here we identify Drosophila fragile X mental retardation protein (dFMRP) as a robust genetic modifier of TDP-43-dependent toxicity in a Drosophila model of ALS. We find that dFMRP overexpression (dFMRP OE) mitigates TDP-43 dependent locomotor defects and reduced lifespan in Drosophila. TDP-43 and FMRP form a complex in flies and human cells. In motor neurons, TDP-43 expression increases the association of dFMRP with stress granules and colocalizes with polyA binding protein in a variant-dependent manner. Furthermore, dFMRP dosage modulates TDP-43 solubility and molecular mobility with overexpression of dFMRP resulting in a significant reduction of TDP-43 in the aggregate fraction. Polysome fractionation experiments indicate that dFMRP OE also relieves the translation inhibition of futsch mRNA, a TDP-43 target mRNA, which regulates neuromuscular synapse architecture. Restoration of futsch translation by dFMRP OE mitigates Futsch-dependent morphological phenotypes at the neuromuscular junction including synaptic size and presence of satellite boutons. Our data suggest a model whereby dFMRP is neuroprotective by remodeling TDP-43 containing RNA granules, reducing aggregation and restoring the translation of specific mRNAs in motor neurons.