Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies.
Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies.
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DOI：
10.1111/jnc.14576
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发表时间：
2019-03
影响因子：
4.7
通讯作者：
Slomnicki LP
中科院分区：
文献类型：
--
作者：
Hetman M;Slomnicki LP
神经系统的发育是通过复杂的基因表达程序进行的，这些基因表达程序在转录和翻译水平上都受到调节。此外，质量控制机制，如TP 53介导的细胞凋亡或神经元活性刺激的存活，确保成功的神经发生和功能回路的形成。在核仁中，核糖体的产生对于蛋白质合成是必不可少的。此外，它还参与染色质组织，并通过核糖体应激反应调节TP 53途径。它的严格调控是维持基因组完整性所必需的。几种核糖体成分和反式作用核糖体生物发生因子的突变导致神经发育综合征，表现为小头畸形、自闭症、智力缺陷和/或进行性神经变性。此外，核糖体生物发生受到干扰神经发育的外源性因素的干扰，包括酒精或寨卡病毒。在这篇综述中，我们提出了最近的文献，认为在各种神经发育综合征的发病机制的核糖体生物合成失调的作用。我们还讨论了潜在的机制，通过这种失调可能会导致发育中的神经系统的细胞病理学，包括不充分的增殖和/或神经祖细胞的损失，未成熟神经元的凋亡，改变神经元形态发生和神经变性。
Development of the nervous system is carried out by complex gene expression programs that are regulated at both transcriptional and translational level. In addition, quality control mechanisms such as the TP53-mediated apoptosis or neuronal activity-stimulated survival ensure successful neurogenesis and formation of functional circuitries. In the nucleolus, production of ribosomes is essential for protein synthesis. In addition, it participates in chromatin organization and regulates the TP53 pathway via the ribosomal stress response. Its tight regulation is required for maintenance of genomic integrity. Mutations in several ribosomal components and trans-acting ribosomal biogenesis factors result in neurodevelopmental syndromes that present with microcephaly, autism, intellectual deficits and/or progressive neurodegeneration. Furthermore, ribosomal biogenesis is perturbed by exogenous factors that disrupt neurodevelopment including alcohol or Zika virus. In this review, we present recent literature that argues for a role of dysregulated ribosomal biogenesis in pathogenesis of various neurodevelopmental syndromes. We also discuss potential mechanisms through which such dysregulation may lead to cellular pathologies of the developing nervous system including insufficient proliferation and/or loss of neuroprogenitors cells, apoptosis of immature neurons, altered neuronal morphogenesis and neurodegeneration.
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