Lipid metabolism in astrocytic structure and function.

Astrocytes are the most abundant glial cell in the central nervous system and are involved in multiple processes including metabolic homeostasis, blood brain barrier regulation and neuronal crosstalk. Astrocytes are the main storage point of glycogen in the brain and it is well established that astrocyte uptake of glutamate and release of lactate prevents neuronal excitability and supports neuronal metabolic function. However, the role of lipid metabolism in astrocytes in relation to neuronal support has been until recently, unclear. Lipids play a fundamental role in astrocyte function, including energy generation, membrane fluidity and cell to cell signaling. There is now emerging evidence that astrocyte storage of lipids in droplets has a crucial physiological and protective role in the central nervous system. This pathway links ß-oxidation in astrocytes to inflammation, signalling, oxidative stress and mitochondrial energy generation in neurons. Disruption in lipid metabolism, structure and signalling in astrocytes can lead to pathogenic mechanisms associated with a range of neurological disorders.

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models.

Mitochondrial dysfunction is a common feature of C9orf72 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 Drosophila models of C9orf72-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 C9orf72 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 Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD.