神经疾病中 RNA 代谢的紊乱及新兴治疗干预措施
Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions.
机构信息
Department of Cellular and Molecular Medicine, Institute for Genomic Medicine, UCSD Stem Cell Program, University of California, San Diego, La Jolla, CA, USA.
Department of Neurology, The Sean M. Healey and AMG Center for ALS at Mass General, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
出版信息
Neuron. 2019 Apr 17;102(2):294-320. doi: 10.1016/j.neuron.2019.03.014.
RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA splicing, transport, and stability. Disruption of RNA binding proteins and widespread RNA processing defects are increasingly recognized as critical determinants of neurological diseases. Here, we describe distinct mechanisms by which the homeostasis of RNA binding proteins is compromised in neurological disorders through their reduced expression level, increased propensity to aggregate or sequestration by abnormal RNAs. These mechanisms all converge toward altered neuronal function highlighting the susceptibility of neurons to deleterious changes in RNA expression and the central role of RNA binding proteins in preserving neuronal integrity. Emerging therapeutic approaches to mitigate or reverse alterations of RNA binding proteins in neurological diseases are discussed.
RNA 结合蛋白通过控制 RNA 加工和运输来维持转录组的稳定性，对于其具有关键作用。这些蛋白的改变会影响 RNA 生命周期的多个步骤，导致各种分子表型，如异常的 RNA 剪接、运输和稳定性。RNA 结合蛋白的破坏和广泛的 RNA 加工缺陷被认为是神经疾病的关键决定因素。在这里，我们通过降低其表达水平、增加聚集倾向或被异常 RNA 隔离等方式，描述了神经紊乱中 RNA 结合蛋白的平衡失调的不同机制。所有这些机制都导致神经元功能改变，突出了神经元对 RNA 表达的有害变化的敏感性，以及 RNA 结合蛋白在维持神经元完整性方面的核心作用。还讨论了减轻或逆转神经疾病中 RNA 结合蛋白改变的新兴治疗方法。
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