Redox homeostasis and inflammation in fibroblasts of patients with Friedreich Ataxia: a possible cross talk.

IF 3.5 3区医学 Q2 NEUROSCIENCES

Frontiers in Molecular Neuroscience Pub Date : 2025-04-16 eCollection Date: 2025-01-01 DOI:10.3389/fnmol.2025.1571402

Andrea Quatrana, Sara Petrillo, Caterina Torda, Eleonora De Santis, Enrico Bertini, Fiorella Piemonte

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引用次数: 0

Abstract

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.

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弗里德赖希共济失调患者成纤维细胞的氧化还原稳态和炎症：可能的串扰。

弗里德赖希共济失调（FRDA）是一种由线粒体蛋白frataxin表达减少引起的神经退行性疾病，氧化还原稳态受损。作为组织氧化还原平衡的主要调节因子，Nrf2在该疾病中存在缺陷，导致细胞铁凋亡。神经炎症是最近出现的FRDA的一个额外的病理机制，必须了解，以便更深入地了解疾病的发病机制。由于Nrf2和NF-kB通路之间的功能性串扰已经被报道过，我们想知道Nrf2缺乏是否会激活FRDA中的炎症。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表达。研究人员发现，患者的TLR4/NF-kB/IL-1β轴显著激活，与氧化还原酶硫氧还蛋白1 （TRX1）和glutaredoxin 1 （GLRX1）的持续增加有关，这是氧化应激条件下激活NF-kB所必需的。此外，我们研究了脂质过氧化的副产物4-HNE在FRDA中作为铁下垂和炎症之间的潜在介质的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Molecular Neuroscience NEUROSCIENCES-

CiteScore

5.70

自引率

2.10%

发文量

669

审稿时长

14 weeks

期刊介绍： Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.