Department of Pathology and Laboratory Medicine, Children's Hospital Philadelphia, Philadelphia, PA, USA.
The Penn Medicine/CHOP Center of Excellence for Friedreich's Ataxia Research, Philadelphia, USA.
Sci Rep. 2018 Mar 22;8(1):5007. doi: 10.1038/s41598-018-23168-x.
Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder caused by decreased expression of frataxin, a protein that localizes to mitochondria and is critical for iron-sulfur-cluster (ISC) assembly. There are no proven effective treatments for FRDA. We previously screened a random shRNA library and identified a synthetic shRNA (gFA11) that reverses the growth defect of FRDA cells in culture. We now report that gFA11 decreases cytokine secretion in primary FRDA fibroblasts and reverts other changes associated with cell senescence. The gene-expression profile induced by gFA11 is remarkably similar to the gene-expression profile induced by the p38 MAPK inhibitor SB203580. We found that p38 phosphorylation, indicating activation of the p38 pathway, is higher in FRDA cells than in normal control cells, and that siRNA knockdown of frataxin in normal fibroblasts also increases p38 phosphorylation. Treatment of FRDA cells with p38 inhibitors recapitulates the reversal of the slow-growth phenotype induced by clone gFA11. These data highlight the involvement of the p38 MAPK pathway in the pathogenesis of FRDA and the potential use of p38 inhibitors as a treatment for FRDA.
弗里德赖希共济失调（FRDA）是一种常染色体隐性遗传性神经和心脏变性疾病，由 frataxin 表达减少引起，frataxin 是一种定位于线粒体的蛋白质，对铁硫簇（ISC）组装至关重要。目前尚无针对 FRDA 的有效治疗方法。我们之前筛选了随机 shRNA 文库，发现了一种合成 shRNA（gFA11），它可以逆转 FRDA 细胞在培养中的生长缺陷。我们现在报告 gFA11 可降低原代 FRDA 成纤维细胞中细胞因子的分泌，并逆转与细胞衰老相关的其他变化。gFA11 诱导的基因表达谱与 p38 MAPK 抑制剂 SB203580 诱导的基因表达谱非常相似。我们发现 FRDA 细胞中的 p38 磷酸化水平（表明 p38 途径的激活）高于正常对照细胞，正常成纤维细胞中 frataxin 的 siRNA 敲低也会增加 p38 磷酸化。用 p38 抑制剂处理 FRDA 细胞可再现 clone gFA11 诱导的生长缓慢表型的逆转。这些数据突出了 p38 MAPK 途径在 FRDA 发病机制中的作用，以及 p38 抑制剂作为 FRDA 治疗方法的潜在用途。
