Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction in C9orf72 ALS/FTD in vivo models and patient iNeurons
Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction in C9orf72 ALS/FTD in vivo models and patient iNeurons
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DOI：
10.1101/2023.10.02.560439
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发表时间：
2023-10
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通讯作者：
Wing Hei Au;Leonor Miller-Fleming;Alvaro Sanchez-Martinez;James A. K. Lee;Madeleine J. Twyning;H. Prag;Sarah Granger;Katie Roome;L. Ferraiuolo;H. Mortiboys;Alexander J. Whitworth
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作者：
Wing Hei Au;Leonor Miller-Fleming;Alvaro Sanchez-Martinez;James A. K. Lee;Madeleine J. Twyning;H. Prag;Sarah Granger;Katie Roome;L. Ferraiuolo;H. Mortiboys;Alexander J. Whitworth
线粒体功能障碍，例如活性氧 (ROS) 的过量产生和线粒体动力学缺陷是 C9orf72 肌萎缩侧索硬化症/额颞叶痴呆 (ALS/FTD) 的常见特征，但目前尚不清楚这些是致病过程的原因还是结果。为了解决这个问题，我们对体内线粒体功能障碍模型进行了全面的表征，分析了 C9orf72 相关病理学的多个转基因果蝇模型，这些模型可能与疾病相关的运动缺陷相关。逆转线粒体破坏不同方面的基因操作表明，只有线粒体 Sod2 和过氧化氢酶等抗氧化剂的基因上调才能挽救 C9orf72 运动缺陷，这表明线粒体功能障碍、ROS 和行为表型之间存在因果关系。通过分析 Keap1/核因子红细胞 2 相关因子 2 (Nrf2) 途径（一种中枢抗氧化反应途径），我们观察到 C9orf72 模型中的反应迟钝。然而，Keap1 的基因减少及其富马酸二甲酯 (DMF) 的药理学靶向能够挽救 C9orf72 相关的运动缺陷。此外，对 C9orf72 患者来源的 iNeurons 的分析显示，ROS 增加，但 DMF 治疗抑制了 ROS 增加。这些结果表明线粒体氧化应激是导致下游线粒体功能障碍（例如线粒体功能和周转改变）的上游致病机制。因此，我们的数据支持将 Keap1/Nrf2 信号通路作为 C9orf72 相关 ALS/FTD 的可行治疗策略。
Mitochondrial dysfunction such as excess production of reactive oxygen species (ROS) and defective mitochondrial dynamics are common features of C9orf72 Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD), but it remains unclear whether these are causative or a consequence of the pathogenic process. To address this, we have performed a comprehensive characterisation of mitochondrial dysfunction in vivo model, analysing multiple transgenic Drosophila models of C9orf72-related pathology, which can be correlated to disease-relevant locomotor deficits. Genetic manipulations to reverse different aspects of mitochondrial disruption revealed that only genetic upregulation of antioxidants such as mitochondrial Sod2 and catalase were able to rescue C9orf72 locomotor deficits, suggesting a causative link between mitochondrial dysfunction, ROS and behavioural phenotypes. By analysing the Keap1/Nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, a central antioxidant response pathway, we observed a blunted response in the C9orf72 models. However, both genetic reduction of Keap1 and its pharmacological targeting by dimethyl fumarate (DMF), was able to rescue C9orf72-related motor deficits. In addition, analysis of C9orf72 patient-derived iNeurons showed increased ROS that was suppressed by DMF treatment. These results indicate that mitochondrial oxidative stress is an upstream pathogenic mechanism leading to downstream mitochondrial dysfunction such as alterations in mitochondrial function and turnover. Consequently, our data support targeting the Keap1/Nrf2 signalling pathway as a viable therapeutic strategy for C9orf72-related ALS/FTD.