PKR-driven ISR signaling controls synaptic translation and structural plasticity in an age-dependent manner.

IF 5.6 2区 医学 Q1 NEUROSCIENCES
Nicolás W Martínez, Felipe Gómez, Ariel Tapia-Godoy, Juan Francisco Roa, Yuwei Liu, Claudia Jara, Cheril Tapia-Rojas, Iván Alfaro, Mauro Costa-Mattioli, Soledad Matus
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引用次数: 0

Abstract

The integrated stress response (ISR) modulates protein homeostasis in response to both intracellular and extracellular signals. The four kinases involved in the ISR all phosphorylate the same target, the alpha subunit of eukaryotic initiation factor 2 (eIF2a), to integrate various stress signals, thereby regulating cell fate. The activation of the ISR reprograms the proteome by inhibiting general protein synthesis while increasing the translation of specific mRNAs. In the brain, the ISR regulates the type of synaptic plasticity necessary for forming long-term memory. More importantly, the activation of the ISR has emerged as a causal mechanism underlying cognitive decline associated with a wide range of neurological disorders, prompting several pharmaceutical companies to target the ISR to promote brain health. However, whether the ISR acts at specific localities within neurons, including synapses, remains unclear. Here, we examined the presence, activity, and spatial arrangement of the ISR branch driven by the double-stranded RNA-dependent protein kinase (PKR) (PKR-eIF2a axis) in synapses and assessed the role of PKR in maintaining synaptic proteostasis over time. Our findings demonstrate that both PKR and eIF2a are localized at synapses, where a dynamic PKR-eIF2a axis regulates synaptic size and the abundance of synaptic proteins in an age-dependent manner. Moreover, PKR deficiency leads to an increase in protein synthesis in synapse-enriched fractions. Thus, the PKR branch of the ISR serves as a new regulator of synaptic structural plasticity.

pkr驱动的ISR信号以年龄依赖的方式控制突触翻译和结构可塑性。
综合应激反应(integrated stress response, ISR)调节蛋白稳态以响应细胞内和细胞外信号。ISR中涉及的四种激酶都磷酸化同一个靶标,即真核起始因子2 (eIF2a)的α亚基,以整合各种应激信号,从而调节细胞命运。ISR的激活通过抑制一般蛋白质合成而增加特定mrna的翻译来重编程蛋白质组。在大脑中,ISR调节形成长期记忆所必需的突触可塑性类型。更重要的是,ISR的激活已经成为与一系列神经系统疾病相关的认知能力下降的因果机制,促使一些制药公司将ISR作为促进大脑健康的目标。然而,ISR是否作用于神经元的特定部位,包括突触,尚不清楚。在这里,我们检测了由双链rna依赖性蛋白激酶(PKR) (PKR- eif2a轴)驱动的ISR分支在突触中的存在、活性和空间排列,并评估了PKR在维持突触蛋白质平衡中的作用。我们的研究结果表明,PKR和eIF2a都定位于突触,其中动态的PKR-eIF2a轴以年龄依赖的方式调节突触大小和突触蛋白的丰度。此外,PKR缺陷导致突触富集部分的蛋白质合成增加。因此,ISR的PKR分支作为突触结构可塑性的新调节器。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neurobiology of Disease
Neurobiology of Disease 医学-神经科学
CiteScore
11.20
自引率
3.30%
发文量
270
审稿时长
76 days
期刊介绍: Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.
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