Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction inC9orf72ALS/FTDin vivomodels and patient iNeurons

Abstract

AbstractMitochondrial dysfunction such as excess production of reactive oxygen species (ROS) and defective mitochondrial dynamics are common features ofC9orf72Amyotrophic 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 dysfunctionin vivomodel, analysing multiple transgenicDrosophilamodels ofC9orf72-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 rescueC9orf72locomotor 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 theC9orf72models. However, both genetic reduction of Keap1 and its pharmacological targeting by dimethyl fumarate (DMF), was able to rescueC9orf72-related motor deficits. In addition, analysis ofC9orf72patient-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 forC9orf72-related ALS/FTD.