Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
J Biol Chem. 2010 Apr 23;285(17):13142-53. doi: 10.1074/jbc.M110.114561. Epub 2010 Feb 25.
Regulated transport and local translation of mRNA in neurons are critical for modulating synaptic strength, maintaining proper neural circuitry, and establishing long term memory. Neuronal RNA granules are ribonucleoprotein particles that serve to transport mRNA along microtubules and control local protein synthesis in response to synaptic activity. Studies suggest that neuronal RNA granules share similar structures and functions with somatic P-bodies. We recently reported that the Huntington disease protein huntingtin (Htt) associates with Argonaute (Ago) and localizes to cytoplasmic P-bodies, which serve as sites of mRNA storage, degradation, and small RNA-mediated gene silencing. Here we report that wild-type Htt associates with Ago2 and components of neuronal granules and co-traffics with mRNA in dendrites. Htt was found to co-localize with RNA containing the 3'-untranslated region sequence of known dendritically targeted mRNAs. Knockdown of Htt in neurons caused altered localization of mRNA. When tethered to a reporter construct, Htt down-regulated reporter gene expression in a manner dependent on Ago2, suggesting that Htt may function to repress translation of mRNAs during transport in neuronal granules.
在神经元中，mRNA 的调控运输和局部翻译对于调节突触强度、维持适当的神经回路和建立长期记忆至关重要。神经元 RNA 颗粒是核糖核蛋白颗粒，用于沿微管运输 mRNA，并响应突触活动控制局部蛋白质合成。研究表明，神经元 RNA 颗粒与体细胞 P 体具有相似的结构和功能。我们最近报道，亨廷顿病蛋白亨廷顿 (Htt) 与 Argonaute (Ago) 结合，并定位于细胞质 P 体，P 体是 mRNA 储存、降解和小 RNA 介导的基因沉默的部位。在这里，我们报告野生型 Htt 与 Ago2 和神经元颗粒的成分结合，并与树突中的 mRNA 共运输。发现 Htt 与包含已知树突靶向 mRNA 的 3'-非翻译区序列的 RNA 共定位。神经元中 Htt 的敲低导致 mRNA 的定位改变。当与报告基因构建体连接时，Htt 以依赖于 Ago2 的方式下调报告基因的表达，表明 Htt 可能在神经元颗粒运输过程中抑制 mRNA 的翻译。
