Department of Pathology and Laboratory Medicine, Children's Hospital Philadelphia, Philadelphia, Pennsylvania 19104, United States.
The Penn Medicine/CHOP Center of Excellence for Friedreich's Ataxia Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
ACS Chem Neurosci. 2020 Sep 2;11(17):2535-2542. doi: 10.1021/acschemneuro.0c00323. Epub 2020 Aug 25.
Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder for which there is no cure or approved treatment. It is characterized by the loss or impaired activity of frataxin protein, which is involved in the biogenesis of iron-sulfur clusters. Our previous studies suggested that cell death in FRDA may involve ferroptosis, an iron-dependent form of cell death requiring lipid peroxidation. Based on reports that oleic acid acts as a ferroptosis inhibitor, we evaluated whether it, other fatty acids, and fatty acid derivatives could rescue viability in cellular models of FRDA. We identified a trifluoromethyl alcohol analog of oleic acid that was significantly more potent than oleic acid itself. Further evaluation indicated that the effects were stereoselective, although a specific molecular target has not yet been identified. This work provides a potential starting point for therapeutics to treat FRDA, as well as a valuable probe molecule to interrogate FRDA pathophysiology.
弗里德赖希共济失调（FRDA）是一种遗传性神经退行性疾病，目前尚无治愈方法或经批准的治疗方法。它的特征是 frataxin 蛋白的丧失或活性受损，frataxin 蛋白参与铁硫簇的生物发生。我们之前的研究表明，FRDA 中的细胞死亡可能涉及铁依赖性细胞死亡形式的 ferroptosis，需要脂质过氧化。基于油酸作为 ferroptosis 抑制剂的报道，我们评估了它、其他脂肪酸和脂肪酸衍生物是否可以挽救 FRDA 细胞模型中的细胞活力。我们鉴定出一种三氟甲醇类似物的油酸，其效力明显高于油酸本身。进一步的评估表明，这些作用是立体选择性的，尽管尚未确定特定的分子靶点。这项工作为治疗 FRDA 的治疗方法提供了一个潜在的起点，同时也是一个有价值的探针分子，可以探究 FRDA 的病理生理学。
