Molecular and Functional Alterations in a Mouse Cardiac Model of Friedreich Ataxia Activation of the Integrated Stress Response, eIF2α Phosphorylation, and the Induction of Downstream Targets
Molecular and Functional Alterations in a Mouse Cardiac Model of Friedreich Ataxia Activation of the Integrated Stress Response, eIF2α Phosphorylation, and the Induction of Downstream Targets
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DOI：
10.1016/j.ajpath.2013.05.032
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发表时间：
2013-09-01
影响因子：
6
通讯作者：
Richardson, Des R.
中科院分区：
文献类型：
--
作者：
Huang, Michael Li-Hsuan;Sivagurunathan, Sutharshani;Richardson, Des R.
弗里德赖希共济失调（FA）是一种神经退行性和心脏退行性疾病，由显著的纤维蛋白缺乏引起。该病以共济失调伴致死性心肌病为特征，但发病机制尚不清楚。我们使用肌肉肌酸激酶条件敲除（KO）小鼠研究了基因表达与进行性组织病理学和功能变化之间的关系；这只小鼠出现了严重的心脏表型，类似于FA患者。我们从3周龄无症状的KO小鼠到10周龄死于疾病的KO小鼠进行了检查。KO小鼠从5周龄开始铁染色阳性，从6周龄开始心功能明显降低。我们发现了一个负责应激诱导的氨基酸生物合成的基因群的早期和显著的上调，并观察到真核翻译起始因子2 α (p-eIF2 α)的磷酸化显著增加，这是一种综合应激反应的激活剂，在3周龄的KO小鼠中，相对于野生型小鼠。重要的是，eIF2 α介导的综合应激反应已经通过下游过程如自噬和细胞凋亡涉及心力衰竭。事实上，在KO小鼠中，一组自噬和凋亡标志物的表达增强。因此，FA心肌病的发病机制与早期和持续的eIF2 α磷酸化有关，该磷酸化在自噬和细胞凋亡激活之前发生。
Friedreich ataxia (FA) is a neurodegenerative and cardiodegenerative disease resulting from marked frataxin deficiency. The condition is characterized by ataxia with fatal cardiomyopathy, but the pathogenic mechanisms are unclear. We investigated the association between gene expression and progressive histopathological and functional changes using the muscle creatine kinase conditional frataxin knockout (KO) mouse; this mouse develops a severe cardiac phenotype that resembles that of FA patients. We examined KO mice from 3 weeks of age, when they are asymptomatic, to 10 weeks of age, when they die of the disease. Positive iron staining was identified in KO mice from 5 weeks of age, with markedly reduced cardiac function from 6 weeks. We identified an early and marked up-regulation of a gene cohort responsible for stress-induced amino acid biosynthesis and observed markedly increased phosphorylation of eukaryotic translation initiation factor 2 alpha (p-eIF2 alpha), an activator of the integrated stress response, in KO mice at 3 weeks of age, relative to wild-type mice. Importantly, the eIF2 alpha-mediated integrated stress response has been previously implicated in heart failure via downstream processes such as autophagy and apoptosis. Indeed, expression of a panel of autophagy and apoptosis markers was enhanced in KO mice. Thus, the pathogenesis of cardiomyopathy in FA correlates with the early and persistent eIF2 alpha phosphorylation, which precedes activation of autophagy and apoptosis.