ABSTRACT

RNA-binding proteins are a critical group of multifunctional proteins that precisely regulate all aspects of gene expression, from alternative splicing to mRNA trafficking, stability, and translation. Converging evidence highlights aberrant RNA metabolism as a common pathogenic mechanism in several neurodevelopmental and neurodegenerative diseases. However, dysregulation of disease-linked RNA-binding proteins results in widespread, often tissue-specific and/or pleiotropic effects on the transcriptome, making it challenging to determine the underlying cellular and molecular mechanisms that contribute to disease pathogenesis. Understanding how splicing misregulation as well as alterations of mRNA stability and localization impact the activity and function of neuronal proteins is fundamental to addressing neurodevelopmental defects and synaptic dysfunction in disease. Here we highlight recent exciting studies that use high-throughput transcriptomic analysis and advanced genetic, cell biological, and imaging approaches to dissect the role of disease-linked RNA-binding proteins on different RNA processing steps. We focus specifically on efforts to elucidate the functional consequences of aberrant RNA processing on neuronal morphology, synaptic activity and plasticity in development and disease. We also consider new areas of investigation that will elucidate the molecular mechanisms RNA-binding proteins use to achieve spatiotemporal control of gene expression for neuronal homeostasis and plasticity.

摘要

RNA 结合蛋白是一组关键的多功能蛋白，可精确调节基因表达的各个方面，从选择性剪接到 mRNA 运输、稳定性和翻译。越来越多的证据强调了异常的 RNA 代谢是几种神经发育和神经退行性疾病的常见致病机制。然而，与疾病相关的 RNA 结合蛋白的失调导致对转录组的广泛的、通常是组织特异性的和/或多效性的影响，使得确定有助于疾病发病机制的潜在细胞和分子机制具有挑战性。了解剪接错误调节以及 mRNA 稳定性和定位的改变如何影响神经元蛋白的活性和功能，对于解决疾病中的神经发育缺陷和突触功能障碍至关重要。在这里，我们重点介绍了最近令人兴奋的研究，这些研究使用高通量转录组学分析和先进的遗传、细胞生物学和成像方法来剖析疾病相关的 RNA 结合蛋白在不同 RNA 加工步骤中的作用。我们特别致力于阐明异常 RNA 加工对神经元形态、突触活动和发育和疾病可塑性的功能后果。