Quatrana Andrea, Petrillo Sara, Torda Caterina, De Santis Eleonora, Bertini Enrico, Piemonte Fiorella
Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Research Unit of Neuromuscular Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Front Mol Neurosci. 2025 Apr 16;18:1571402. doi: 10.3389/fnmol.2025.1571402. eCollection 2025.
Redox homeostasis is impaired in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2, the master regulator of tissue redox balance, is defective in the disease, driving cells to ferroptosis. Neuro-inflammation is recently emerging as an additional pathological mechanism in FRDA and has to be understood in order to go deeper into the pathogenesis of the disease. As a functional cross talk between Nrf2 and NF-kB pathways has been previously reported, we wonder if inflammation may be activated in FRDA as a consequence of Nrf2 deficiency. Thus, we analyzed the expression of proteins involved in the antioxidant and inflammatory responses in fibroblasts of patients with FRDA. We found a significant activation of the TLR4/NF-kB/IL-1β axis in patients, associated to a consistent increase of the redox enzymes thioredoxin 1 (TRX1) and glutaredoxin 1 (GLRX1), which are essential to activate NF-kB under oxidative stress conditions. Furthermore, we investigated the role of 4-HNE, a by-product of lipid peroxidation, as a potential mediator between ferroptosis and inflammation in FRDA.
氧化还原稳态在弗里德赖希共济失调（FRDA）中受损，这是一种由线粒体蛋白铁硫蛋白表达降低引起的神经退行性疾病。Nrf2是组织氧化还原平衡的主要调节因子，在该疾病中存在缺陷，促使细胞发生铁死亡。神经炎症最近作为FRDA中的另一种病理机制出现，为了更深入地了解该疾病的发病机制，必须对其进行研究。由于先前已报道Nrf2和NF-κB途径之间存在功能性相互作用，我们想知道炎症是否可能由于Nrf2缺乏而在FRDA中被激活。因此，我们分析了FRDA患者成纤维细胞中参与抗氧化和炎症反应的蛋白质表达。我们发现患者中TLR4/NF-κB/IL-1β轴显著激活，这与氧化还原酶硫氧还蛋白1（TRX1）和谷氧还蛋白1（GLRX1）的持续增加相关，这两种酶在氧化应激条件下激活NF-κB至关重要。此外，我们研究了脂质过氧化的副产物4-羟基壬烯醛（4-HNE）作为FRDA中铁死亡和炎症之间潜在介质的作用。
