Activation of the Keap1/Nrf2 Pathway Suppresses Mitochondrial Dysfunction, Oxidative Stress, and Motor Phenotypes in ALS/FTD Models

Mitochondrial dysfunction is a common feature of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several models of -ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of or pharmacological inhibition by dimethyl fumarate significantly rescued the -related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for -related ALS/FTD.