Fragile X mental retardation protein in the driver's seat.
Fragile X mental retardation protein in the driver's seat.
复制标题
驾驶座上的脆性X智障蛋白。
DOI：
10.1093/cercor/bhp089
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Brenman,JayE
中科院分区：
文献类型：
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作者：
Brenman,JayE
脆性X染色体综合征（FXS）是精神发育迟滞的最常见单基因病因，与脆性X染色体精神发育迟滞1基因FMR 1突变密切相关（Fu et al. 1991; Verkerk et al. 1991; Feng et al. 1997; Musumeci et al. 1999; Hagerman et al. 2009）。然而，鉴定FMR 1蛋白产物FMRP（脆性X智力低下蛋白）丢失的后果已被证明是困难的。在这一期的《大脑皮层》中，Curia等人和Qiu等人的两篇论文，证明FMRP通常导航海马兴奋和抑制的危险道路，控制c-氨基丁酸能（GABA能）制动器和海马能加速器。FMRP是一种RNA结合蛋白，可能调节数千个基因（阿什利等，1993;布朗等，2001）。因此，确定不同FXS表型的分子机制仍然具有挑战性。FMRP不仅调节细胞体中的翻译（Khandjian et al. 1996）;它还被转运到树突以影响局部RNA加工。其他提出的FMRP功能包括mRNA转运，包括GABAA亚基mRNA和mRNA稳定性（Zalfa et al. 2007）。FMRP功能丧失的后果可能超出翻译调控范围：它还可以在RNA诱导沉默复合物（RISC）核酸酶复合物中发挥作用，通过调节小干扰RNA影响mRNA的翻译（Caudy et al. 2002; Ishizuka et al. 2002）。这种分子的复杂性表明，功能评估的局部电路和突触活动的动物模型FXS，而不是基因的基因分析，可能会完善的假设的分子靶点FMRP功能丧失及其对脑功能障碍的贡献。
Fragile X syndrome (FXS), the most common single gene cause of mental retardation, is securely associated with mutations in the fragile X mental retardation 1 gene, FMR1 (Fu et al. 1991; Verkerk et al. 1991; Feng et al. 1997; Musumeci et al. 1999; Hagerman et al. 2009). Nevertheless, identification of consequences of loss of the protein product of FMR1, the fragile X mental retardation protein FMRP, has proven difficult. In this issue of Cerebral Cortex, 2 papers, one by Curia et al. and the other by Qiu et al., demonstrate that FMRP normally navigates the treacherous road of hippocampal excitation and inhibition, controlling the c-aminobutyric acidergic (GABAergic) brakes and glutamatergic accelerator. Without FMRP in the driver’s seat, the journey becomes perilous, resulting in excess excitation and enhanced seizure vulnerability.FMRP, an RNA-binding protein, potentially regulates thousands of genes (Ashley et al. 1993; Brown et al. 2001). Thus, determining molecular mechanisms for diverse FXS phenotypes remains challenging. FMRP not only regulates translation in the cell body (Khandjian et al. 1996); it is also transported to dendrites to influence local RNA processing. Other proposed FMRP functions include mRNA transport, including GABAA subunit mRNA and mRNA stability (Zalfa et al. 2007). Consequences of FMRP loss of function may extend beyond translation regulation: It can also function in the RNA induced silencing complex (RISC) nuclease complex influencing translation of mRNAs through regulation of small interfering RNAs (Caudy et al. 2002; Ishizuka et al. 2002). This molecular complexity suggests that functional assessment of local circuits and synaptic activity in animal models of FXS—rather than gene-by-gene analysis—may refine hypotheses of molecular targets of FMRP loss of function and their contribution to brain dysfunction.