Friedreich's ataxia (FRDA) is a hereditary and predominantly neurodegenerative disease caused by a deficiency of the protein frataxin (FXN). As part of the overall efforts to understand the molecular basis of neurodegeneration in FRDA, a new human neural cell line with doxycycline-induced FXN knockdown was established. This cell line, hereafter referred to as iFKD-SY, is derived from the human neuroblastoma SH-SY5Y and retains the ability to differentiate into mature neuron-like cells. In both proliferating and differentiated iFKD-SY cells, the induction of FXN deficiency is accompanied by increases in oxidative stress and DNA damage, reduced aconitase enzyme activity, higher levels of p53 and p21, activation of caspase-3, and subsequent apoptosis. More interestingly, FXN-deficient iFKD-SY cells exhibit an important transcriptional deregulation in many of the genes implicated in DNA repair pathways. The levels of some crucial proteins involved in DNA repair appear notably diminished. Furthermore, similar changes are found in two additional neural cell models of FXN deficit: primary cultures of FXN-deficient mouse neurons and human olfactory mucosa stem cells obtained from biopsies of FRDA patients. These results suggest that the deficiency of FXN leads to a down-regulation of DNA repair pathways that synergizes with oxidative stress to provoke DNA damage, which may be involved in the pathogenesis of FRDA. Thus, a failure in DNA repair may be considered a shared common molecular mechanism contributing to neurodegeneration in a number of hereditary ataxias including FRDA.

弗里德赖希共济失调 (FRDA) 是一种遗传性的、主要是神经退行性疾病，由蛋白质 frataxin (FXN) 缺乏引起。作为了解 FRDA 神经变性分子基础的整体努力的一部分，建立了一种新的人类神经细胞系，该细胞系具有多西环素诱导的 FXN 敲低。该细胞系（以下称为 iFKD-SY）源自人神经母细胞瘤 SH-SY5Y，保留了分化为成熟神经元样细胞的能力。在增殖和分化的 iFKD-SY 细胞中，FXN 缺乏的诱导伴随着氧化应激和 DNA 损伤的增加、乌头酸酶活性降低、p53 和 p21 水平升高、caspase-3 激活以及随后的细胞凋亡。更有趣的是，FXN 缺陷的 iFKD-SY 细胞在许多涉及 DNA 修复途径的基因中表现出重要的转录失调。一些参与 DNA 修复的关键蛋白质的水平似乎显着降低。此外，在另外两种 FXN 缺陷神经细胞模型中也发现了类似的变化：FXN 缺陷小鼠神经元的原代培养物和从 FRDA 患者活检中获得的人类嗅粘膜干细胞。这些结果表明，FXN 的缺乏会导致 DNA 修复途径的下调，与氧化应激协同作用，引发 DNA 损伤，这可能与 FRDA 的发病机制有关。因此，DNA 修复失败可能被认为是导致包括 FRDA 在内的许多遗传性共济失调神经变性的共同分子机制。