SS-31 efficacy in a mouse model of Friedreich ataxia by upregulation of frataxin expression
SS-31 efficacy in a mouse model of Friedreich ataxia by upregulation of frataxin expression
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SS-31 通过上调 frataxin 表达对 Friedreich 共济失调小鼠模型产生功效
DOI：
10.1093/hmg/ddab232
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发表时间：
2021-08-13
影响因子：
3.5
通讯作者：
Li, Kuanyu
中科院分区：
文献类型：
--
作者：
Liu, Yutong;Cai, Jing;Li, Kuanyu
Friedreich共济失调(Friedreich ataxia，FRDA)是一种严重的遗传性神经退行性疾病，多伴有肥厚性心肌病，由Frataxin(FXN)表达减少引起。然而，仍然没有有效的治疗方法。我们先前的研究表明，线粒体靶向性多肽SS-31能够上调FXN的表达，改善FRDA患者细胞的线粒体功能。为了进一步探索SS-31的潜力，我们使用了基于GAA扩展的模型，包括Y47和YG8R(FXN Kiko)小鼠、小鼠的原代神经元和巨噬细胞以及FRDA患者的细胞。每日1次腹腔注射SS-31 1 mg/kg，连续1个月，观察大鼠运动功能明显改善。SS-31治疗后，背根神经节空泡化、齿状核病变及脊髓髓鞘厚度丢失均得到修复。此外，肥大的心肌细胞和散乱排列的异常浦肯野细胞显著减少。有趣的是，我们发现SS-31处理不仅在细胞培养中观察到的翻译水平上调了FXN的表达，而且在体内也在mRNA水平上上调了FXN的表达。因此，所有受试组织的线粒体形态和功能都得到了极大的改善。重要的是，我们的数据提供了额外的证据，表明维持治疗益处需要持续给药。综上所述，我们的研究结果证明了SS-31通过上调FXN在体内的治疗效果，并为FRDA的临床应用提供了潜在的指导。
Friedreich ataxia (FRDA) is a serious hereditary neurodegenerative disease, mostly accompanied with hypertrophic cardiomyopathy, caused by the reduced expression of frataxin (FXN). However, there is still no effective treatment. Our previous studies have shown that SS-31, a mitochondrion-targeted peptide, is capable to upregulate the expression of FXN and improve the mitochondrial function in cells derived from FRDA patients. To further explore the potential of SS-31, we used the GAA expansion-based models, including Y47 and YG8R (Fxn KIKO) mice, primary neurons and macrophages from the mice and cells derived from FRDA patients. After once-daily intraperitoneal injection of 1 mg/kg SS-31 for 1 month, we observed the significant improvement of motor function. The vacuolation in dorsal root ganglia, lesions in dentate nuclei and the lost thickness of myelin sheath of spinal cord were all repaired after SS-31 treatment. In addition, the hypertrophic cardiomyocytes and disarrayed abnormal Purkinje cells were dramatically reduced. Interestingly, we found that SS-31 treatment upregulated FXN expression not only at the translational levels as observed in cell culture but also at mRNA levels in vivo. Consequently, mitochondrial morphology and function were greatly improved in all tested tissues. Importantly, our data provided additional evidence that the maintenance of the therapeutic benefits needed continuous drug administration. Taken together, our findings have demonstrated the effectiveness of SS-31 treatment through the upregulation of FXN in vivo and offer guidance of the potential usage in the clinical application for FRDA.