Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor
Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor
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DOI：
10.1093/hmg/ddw308
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发表时间：
2016-11-15
影响因子：
3.5
通讯作者：
Pandolfo, Massimo
中科院分区：
文献类型：
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作者：
Codazzi, Franca;Hu, Amelie;Pandolfo, Massimo
我们分别利用从弗里德赖希共济失调（FRDA）患者和健康受试者（FRDA神经元和CT神经元）中获得的诱导多能干细胞（iPSC）来源的神经元来揭示与frataxin （FXN）缺乏相关的表型改变，并研究是否可以通过上调FXN的治疗来逆转这些改变。FRDA和对照iPSCs同样能够分化为神经元或星形细胞表型。与CT神经元相比，FRDA神经元表现出较低的铁硫（Fe-S）和含硫酸蛋白水平，较高的不稳定铁池（LIP），较高的线粒体超氧化物歧化酶（SOD2）表达，活性氧（ROS）增加，还原型谷胱甘肽（GSH）水平降低，对氧化剂的敏感性增强，表明Fe-S簇生物发生不足，铁代谢改变，氧化应激。用苯甲酰胺HDAC抑制剂109显著上调FXN表达，增加含Fe-S和硫辛酸的蛋白水平，下调SOD2水平，使LIP和ROS水平正常化，并几乎完全保护FRDA神经元免受氧化应激介导的细胞死亡。我们的研究结果表明，纠正FXN缺陷不仅可以阻止疾病进展，还可以通过挽救仍然存活的功能失调神经元来改善临床。
We employed induced pluripotent stem cell (iPSC)-derived neurons obtained from Friedreich ataxia (FRDA) patients and healthy subjects, FRDA neurons and CT neurons, respectively, to unveil phenotypic alterations related to frataxin (FXN) deficiency and investigate if they can be reversed by treatments that upregulate FXN. FRDA and control iPSCs were equally capable of differentiating into a neuronal or astrocytic phenotype. FRDA neurons showed lower levels of iron-sulfur (Fe-S) and lipoic acid-containing proteins, higher labile iron pool (LIP), higher expression of mitochondrial superoxide dismutase (SOD2), increased reactive oxygen species (ROS) and lower reduced glutathione (GSH) levels, and enhanced sensitivity to oxidants compared with CT neurons, indicating deficient Fe-S cluster biogenesis, altered iron metabolism, and oxidative stress. Treatment with the benzamide HDAC inhibitor 109 significantly upregulated FXN expression and increased Fe-S and lipoic acid-containing protein levels, downregulated SOD2 levels, normalized LIP and ROS levels, and almost fully protected FRDA neurons from oxidative stress-mediated cell death. Our findings suggest that correction of FXN deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.