Activation of an Endogenous Suicide Response after Perturbation of rRNA Synthesis Leads to Neurodegeneration in Mice
Activation of an Endogenous Suicide Response after Perturbation of rRNA Synthesis Leads to Neurodegeneration in Mice
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DOI：
10.1523/jneurosci.2439-08.2008
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发表时间：
2008-11-26
影响因子：
5.3
通讯作者：
Schuetz, Guenther
中科院分区：
文献类型：
--
作者：
Parlato, Rosanna;Kreiner, Grzegorz;Schuetz, Guenther
rRNA基因的转录对于维持核仁的完整性是必不可少的，核仁的完整性是细胞健康状态和增殖速率的标志。rRNA合成的抑制导致核仁解体，p53水平升高，并诱导细胞自杀，将核仁确定为关键的应激传感器。然而，rRNA合成的失调是否通过促进细胞死亡和/或通过抑制细胞生长而因果地参与神经变性尚未解决。转录因子TIF-IA在哺乳动物rRNA合成中起着重要作用，调节RNA聚合酶I的转录活性。为了研究神经系统中核仁扰动的后果，我们选择在两种不同的情况下特异性地消融编码转录因子TIF-IA的基因：神经祖细胞和海马神经元。在这里，我们表明，消融TIF-IA导致受损的核仁活性，并导致在神经祖细胞和海马神经元中的促凋亡转录因子p53的水平增加，但只在神经祖细胞中诱导快速凋亡。成年海马的非分裂细胞更难失去rRNA转录，并面临着长期的退化。我们的研究提供了一个未开发的策略，启动基于核仁功能的扰动神经退行性变，并强调了一个新的角度来研究参与神经退行性过程的细胞和分子的变化。
Transcription of rRNA genes is essential for maintaining nucleolar integrity, a hallmark for the healthy state and proliferation rate of a cell. Inhibition of rRNA synthesis leads to disintegration of the nucleolus, elevated levels of p53, and induction of cell suicide, identifying the nucleolus as a critical stress sensor. Whether deregulation of rRNA synthesis is causally involved in neurodegeneration by promoting cell death and/or by inhibiting cellular growth has however not been addressed. The transcription factor TIF-IA plays a central role in mammalian rRNA synthesis, regulating the transcriptional activity of RNA polymerase I. To investigate the consequences of nucleolar perturbation in the nervous system, we have chosen to specifically ablate the gene encoding the transcription factor TIF-IA in two different contexts: neural progenitors and hippocampal neurons. Here, we show that ablation of TIF-IA leads to impaired nucleolar activity and results in increased levels of the proapoptotic transcription factor p53 in both neural progenitors and hippocampal neurons but induces rapid apoptosis only in neural progenitors. Nondividing cells of the adult hippocampus are more refractory to loss of rRNA transcription and face a protracted degeneration. Our study provides an unexploited strategy to initiate neurodegeneration based on perturbation of nucleolar function and underscores a novel perspective to study the cellular and molecular changes involved in the neurodegenerative processes.