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首页> 外文期刊>Neurobiology of disease >Fragile X Mental Retardation Protein positively regulates PKA anchor Rugose and PKA activity to control actin assembly in learning/memory circuitry
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Fragile X Mental Retardation Protein positively regulates PKA anchor Rugose and PKA activity to control actin assembly in learning/memory circuitry

机译：脆弱的X精神发育迟滞蛋白质呈正常调节PKA锚固rugose和PKA活动，以控制学习/存储器电路中的肌动蛋白组件

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摘要

Recent work shows Fragile X Mental Retardation Protein (FMRP) drives the translation of very large proteins ( > 2000 aa) mediating neurodevelopment. Loss of function results in Fragile X syndrome (FXS), the leading heritable cause of intellectual disability (ID) and autism spectrum disorder (ASD). Using the Drosophila FXS disease model, we discover FMRP positively regulates the translation of the very large A-Kinase Anchor Protein (AKAP) Rugose ( > 3000 aa), homolog of ASD-associated human Neurobeachin (NBEA). In the central brain Mushroom Body (MB) circuit, where Protein Kinase A (PKA) signaling is necessary for learning/memory, FMRP loss reduces Rugose levels and targeted FMRP overexpression elevates Rugose levels. Using a new in vivo transgenic PICA activity reporter (PICA-SPARK), we find FMRP loss reduces PKA activity in MB Kenyon cells whereas FMRP overexpression elevates PKA activity. Consistently, loss of Rugose reduces PKA activity, but Rugose overexpression has no independent effect. A well-established PICA output is regulation of F-actin cytoskeleton dynamics. In the FXS disease model, F-actin is aberrantly accumulated in MB lobes and single MB Kenyon cells. Consistently, Rugose loss results in similar F-actin accumulation. Moreover, targeted FMRP, Rugose and PKA overexpression all result in increased F-actin accumulation in the MB circuit. These findings uncover a FMRP-Rugose-PKA mechanism regulating actin cytoskeleton. This study reveals a novel FMRP mechanism controlling neuronal PKA activity, and demonstrates a shared mechanistic connection between FXS and NBEA associated ASD disease states, with a common link to PICA and F-actin misregulation in brain neural circuits.
机译：最近的工作表明脆弱的X精神迟发蛋白（FMRP）驱动介导神经发育的非常大的蛋白质（> 2000AA）的翻译。功能丧失导致脆弱的X综合征（FXS），知识分子残疾（ID）和自闭症谱系（ASD）的主要遗传原因。使用果蝇FXS疾病模型，我们发现FMRP积极调节非常大的A-kinase Anchor蛋白（Akap）rugose（> 3000Aa）的翻译，Asd相关人体Neurobeanin（NBEA）的同源物。在中央脑蘑菇体（MB）电路中，在学习/记忆需要蛋白激酶A（PKA）信号传导的情况下，FMRP损失减少了rugose水平，并且靶向FMRP过表达升高了Rugose水平。使用新的体内转基因Pica活性报告者（Pica-Spark），我们发现FMRP损失降低了MB kenyon细胞中的PKA活性，而FMRP过表达升高了PKA活性。始终如一地，Rugose的丧失降低了PKA活性，但Rugose过表达没有独立的效果。良好的PICA输出是对F-actin细胞骨架动力学的调节。在FXS疾病模型中，F-actin在Mb裂片和单一MB kenyon细胞中处于异常累积。一致地，粗糙损失导致相似​​的F-actin积累。此外，靶向的FMRP，Rugose和PKA过度表达均导致MB电路中的F-Actin积累增加。这些发现发现了调节肌动蛋白细胞骨架的FMRP-Rugose-PKA机制。该研究揭示了一种控制神经元PKA活性的新型FMRP机制，并证明了FXS和NBEA相关ASD疾病状态之间的共同机械连接，具有脑神经电路中的PICA和F-Actin误解的共同链接。

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