A TAT-Frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model
A TAT-Frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model
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DOI：
10.1093/hmg/ddr554
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发表时间：
2012-03-15
影响因子：
3.5
通讯作者：
Payne, R. Mark
中科院分区：
文献类型：
--
作者：
Vyas, Piyush M.;Tomamichel, Wendy J.;Payne, R. Mark
弗里德赖希共济失调（FRDA）是最常见的遗传性人类共济失调，并且是由在细胞核中编码的线粒体蛋白共济失调蛋白（FXN）缺乏引起的。这种缺陷与铁硫（FeS）簇酶缺陷相关，导致进行性共济失调和经常致命的心肌病。无药可救。为了确定线粒体中缺失的FXN蛋白的外源性替代是否会修复缺陷，我们使用转录反式激活因子（达特）蛋白转导结构域将人FXN蛋白递送到培养的患者细胞和FRDA严重小鼠模型的线粒体。TATFXN融合蛋白在体外结合铁，转导到FRDA缺陷成纤维细胞的线粒体中，并减少响应外源性铁氧化应激的半胱天冬酶-3活化。将TATFXN蛋白注射到FXN条件性丧失的小鼠中，增加了它们的生长速度和平均寿命53，增加了它们的平均心率和心输出量，增加了乌头酸酶的活性，逆转了心脏中异常的线粒体增殖和超微结构。这些结果表明，细胞渗透肽能够在体内递送功能性线粒体蛋白以挽救非常严重的疾病表型，并提出了TATFXN作为蛋白质替代疗法的可能性。
Friedreichs ataxia (FRDA) is the most common inherited human ataxia and results from a deficiency of the mitochondrial protein, frataxin (FXN), which is encoded in the nucleus. This deficiency is associated with an ironsulfur (FeS) cluster enzyme deficit leading to progressive ataxia and a frequently fatal cardiomyopathy. There is no cure. To determine whether exogenous replacement of the missing FXN protein in mitochondria would repair the defect, we used the transactivator of transcription (TAT) protein transduction domain to deliver human FXN protein to mitochondria in both cultured patient cells and a severe mouse model of FRDA. A TATFXN fusion protein bound iron in vitro, transduced into mitochondria of FRDA deficient fibroblasts and reduced caspase-3 activation in response to an exogenous iron-oxidant stress. Injection of TATFXN protein into mice with a conditional loss of FXN increased their growth velocity and mean lifespan by 53 increased their mean heart rate and cardiac output, increased activity of aconitase and reversed abnormal mitochondrial proliferation and ultrastructure in heart. These results show that a cell-penetrant peptide is capable of delivering a functional mitochondrial protein in vivo to rescue a very severe disease phenotype, and present the possibility of TATFXN as a protein replacement therapy.