Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment
Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment
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DOI：
10.1111/jcmm.13365
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发表时间：
2018-02-01
影响因子：
5.3
通讯作者：
Ros, Joaquim
中科院分区：
文献类型：
--
作者：
Britti, Elena;Delaspre, Fabien;Ros, Joaquim
弗里德赖希共济失调（FA）是一种罕见的疾病引起的缺乏共济失调，线粒体蛋白。由于没有治愈这种疾病的方法，已经开发了许多策略来减少这种缺乏的有害影响。这些方法之一是基于通过将蛋白质偶联至转录的反式激活因子（达特）肽而将共济失调蛋白递送至组织，这使得细胞膜能够穿过。在这项研究中，我们测试了TAT-MTScs-FXN融合蛋白减少从背根神经节（DRG）（受影响最严重的组织之一）获得的共济失调蛋白耗尽的神经元上的神经变性标志物的效率。在该疾病的小鼠模型中，我们测试了TAT-MTScs-FXN穿透线粒体的能力及其对寿命的影响。在DRG神经元中，用TAT-MTScs-FXN处理增加了细胞存活，减少了神经突变性并减少了凋亡标志物，例如α-胞衬蛋白裂解和半胱天冬酶9活化。此外，我们表明，热休克蛋白60（HSP 60），一种针对线粒体的分子伴侣，在共济失调蛋白缺乏的神经元中受到损害的处理，这是由TAT-MTScs-FXN另外缓解。在该疾病的小鼠模型中，TAT-MTScs-FXN的施用能够到达肌肉线粒体，恢复琥珀酸脱氢酶的活性并产生显著的寿命增加。这些结果支持使用TAT-MTScs-FXN作为弗里德赖希共济失调的治疗。
Friedreich ataxia (FA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein. As there is no cure available for this disease, many strategies have been developed to reduce the deleterious effects of such deficiency. One of these approaches is based on delivering frataxin to the tissues by coupling the protein to trans-activator of transcription (TAT) peptides, which enables cell membranes crossing. In this study, we tested the efficiency of TAT-MTScs-FXN fusion protein to decrease neurodegeneration markers on frataxin-depleted neurons obtained from dorsal root ganglia (DRG), one of the most affected tissues. In mice models of the disease, we tested the ability of TAT-MTScs-FXN to penetrate the mitochondria and its effect on lifespan. In DRG neurons, treatment with TAT-MTScs-FXN increased cell survival, decreased neurite degeneration and reduced apoptotic markers, such as alpha-fodrin cleavage and caspase 9 activation. Also, we show that heat-shock protein 60 (HSP60), a molecular chaperone targeted to mitochondria, suffered an impaired processing in frataxin-deficient neurons that was relieved by TAT-MTScs-FXN addition. In mice models of the disease, administration of TAT-MTScs-FXN was able to reach muscle mitochondria, restore the activity of the succinate dehydrogenase and produce a significant lifespan increase. These results support the use of TAT-MTScs-FXN as a treatment for Friedreich ataxia.