The hexanucleotide expansion of the C9orf72 gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from C9orf72 patients and control subjects by examining the mRNA levels of 84 redox-related genes. The expression of ten redox genes was altered in samples from C9orf72 ALS patients compared to healthy controls. Considering that Nuclear factor erythroid 2-Related Factor 2 (NRF2) modulates the expression of a wide range of redox genes, we further investigated its status on an in vitro model of dipeptide repeat (DPR) toxicity. This model mimics the gain of function, toxic mechanisms attributed to C9orf72 pathology. We found that exposure to DPRs increased superoxide levels and reduced mitochondrial potential as well as cell survival. Importantly, cells overexpressing DPRs exhibited reduced protein levels of NRF2 and its target genes upon inhibition of the proteasome or its canonical repressor, the E3 ligase adapter KEAP1. However, NRF2 activation was sufficient to recover cell viability and redox homeostasis. This study identifies NRF2 as a putative target in precision medicine for the therapy of ALS patients harboring C9orf72 expansion repeats.

中文翻译：

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C9orf72-ALS 中的二肽重复病理学与氧化还原、线粒体和 NRF2 通路失衡有关

在 40% 的家族性肌萎缩侧索硬化症 (ALS) 患者中发现了C9orf72基因的六核苷酸扩增。这种遗传改变与活性氧物质的管理受损有关。在这项研究中，我们通过检查 84 个氧化还原相关基因的 mRNA 水平，对来自C9orf72患者和对照受试者的白细胞进行了靶向转录分析。来自C9orf72的样本中十个氧化还原基因的表达发生了改变ALS 患者与健康对照组相比。考虑到核因子红细胞 2 相关因子 2 (NRF2) 可调节多种氧化还原基因的表达，我们进一步研究了其在二肽重复 (DPR) 毒性体外模型中的状态。该模型模仿C9orf72的功能获得、毒性机制病理。我们发现暴露于 DPRs 会增加超氧化物水平并降低线粒体电位和细胞存活率。重要的是，过表达 DPR 的细胞在抑制蛋白酶体或其典型阻遏物 E3 连接酶接头 KEAP1 后表现出 NRF2 及其靶基因的蛋白质水平降低。然而，NRF2 激活足以恢复细胞活力和氧化还原稳态。这项研究将 NRF2 确定为精准医学的推定靶点，用于治疗携带C9orf72扩增重复序列的 ALS 患者。