Aberrant RNA translation in fragile X syndrome: From FMRP mechanisms to emerging therapeutic strategies.
Aberrant RNA translation in fragile X syndrome: From FMRP mechanisms to emerging therapeutic strategies.
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DOI：
10.1016/j.brainres.2018.04.008
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发表时间：
2018-08-15
期刊：
影响因子：
2.9
通讯作者：
Bassell GJ
中科院分区：
文献类型：
--
作者：
Banerjee A;Ifrim MF;Valdez AN;Raj N;Bassell GJ
过去几十年的研究揭示了脆性X染色体智力低下蛋白（FMRP）的多方面作用，以及它的缺失如何导致脆性X染色体综合征（FXS）的病理生理学。在FXS的小鼠模型中通常观察到通过第1组代谢型谷氨酸受体的过度信号传导，这部分归因于失调的翻译和下游信号传导。考虑到FMRP的丧失通常可以影响的细胞和生理功能的广泛范围，可能有利的是追求直接靶向调节蛋白质合成的翻译组分或信号传导因子的基于疾病机制的治疗。因此，正在研究翻译机制上游和下游的各种FMRP靶点，以进一步了解FXS中RNA和蛋白质合成失调的分子机制，并测试其作为治疗干预措施以缓解FXS相关症状的潜在作用。在这篇综述中，我们将广泛讨论最近取得的进展，了解FMRP在翻译调控中的作用，新的临床前动物模型与FMRP的目标位于不同水平的翻译和信号转导途径的治疗干预，以及未来使用干细胞模型FXS相关的表型。
Research in the past decades has unfolded the multifaceted role of Fragile X mental retardation protein (FMRP) and how its absence contributes to the pathophysiology of Fragile X syndrome (FXS). Excess signaling through group 1 metabotropic glutamate receptors is commonly observed in mouse models of FXS, which in part is attributed to dysregulated translation and downstream signaling. Considering the wide spectrum of cellular and physiologic functions that loss of FMRP can affect in general, it may be advantageous to pursue disease mechanism based treatments that directly target translational components or signaling factors that regulate protein synthesis. Various FMRP targets upstream and downstream of the translational machinery are therefore being investigated to further our understanding of the molecular mechanism of RNA and protein synthesis dysregulation in FXS as well as test their potential role as therapeutic interventions to alleviate FXS associated symptoms. In this review, we will broadly discuss recent advancements made towards understanding the role of FMRP in translation regulation, new pre-clinical animal models with FMRP targets located at different levels of the translational and signal transduction pathways for therapeutic intervention as well as future use of stem cells to model FXS associated phenotypes.
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