RNA-binding proteins, neural development and the addictions.
RNA-binding proteins, neural development and the addictions.
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DOI：
10.1111/gbb.12273
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Yazdani N
中科院分区：
文献类型：
--
作者：
Bryant CD;Yazdani N
基因表达的转录和转录后调控定义了将遗传和环境风险因素与成瘾背后的神经行为功能障碍联系起来的神经生物学机制。真核生物基因组中超过 1000 个基因编码多功能 RNA 结合蛋白 (RBP)，可调节 RNA 生物合成的各个水平。超过 50% 的 RBP 在大脑中表达，它们在发育和成年期间调节 RNA 的选择性剪接、运输、定位、稳定性和翻译。 RBP 功能障碍可以对其靶标产生全局影响，这些靶标是阿尔茨海默病和帕金森病等神经退行性疾病以及自闭症和精神分裂症等神经发育障碍的基础。在这里，我们考虑 RBP 影响成瘾背后的关键分子靶标、神经发育、突触可塑性和神经行为功能障碍的证据。人类和哺乳动物模型生物体中日益强大的全基因组关联研究，结合更加精确的转录组学和蛋白质组学方法，将继续揭示 RBP 在成瘾中的新颖且可能具有选择性的作用。主要挑战包括识别整个亚细胞空间（例如，核剪接组与突触翻译组）和时间的特定细胞类型的动态 RBP 靶标的生物学功能，并通过转录后修饰操纵 RBP 程序，以防止或逆转成瘾背后的异常神经发育和可塑性。
Transcriptional and post-transcriptional regulation of gene expression defines the neurobiological mechanisms that bridge genetic and environmental risk factors with neurobehavioral dysfunction underlying the addictions. More than 1000 genes in the eukaryotic genome code for multifunctional RNA binding proteins (RBPs) that can regulate all levels of RNA biogenesis. More than 50% of these RBPs are expressed in the brain where they regulate alternative splicing, transport, localization, stability, and translation of RNAs during development and adulthood. RBP dysfunction can exert global effects on their targetomes that underlie neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease as well as neurodevelopmental disorders, including autism and schizophrenia. Here, we consider the evidence that RBPs influence key molecular targets, neurodevelopment, synaptic plasticity, and neurobehavioral dysfunction underlying the addictions. Increasingly well-powered genome-wide association studies in humans and mammalian model organisms combined with ever more precise transcriptomic and proteomic approaches will continue to uncover novel and possibly selective roles for RBPs in the addictions. Key challenges include identifying the biological functions of the dynamic RBP targetomes from specific cell types throughout subcellular space (e.g., the nuclear spliceome versus the synaptic translatome) and time and manipulating RBP programs through post-transcriptional modifications to prevent or reverse aberrant neurodevelopment and plasticity underlying the addictions.