This study investigates the role of mutant SOD1 in astrocytes and its impact on disease progression in amyotrophic lateral sclerosis (ALS). Using LoxSOD1G37R mice, which can be made to delete the mutant SOD1 gene specifically in astrocytes, the researchers found that reducing mutant SOD1 expression in astrocytes did not affect the onset of disease but significantly delayed microglial activation and slowed later disease progression. This suggests that mutant astrocytes are viable targets for therapies aimed at slowing the non-cell-autonomous killing of motor neurons in ALS. The findings also highlight the importance of astrocytes in modulating the inflammatory response through microglial activation, providing insights into potential therapeutic strategies.This study investigates the role of mutant SOD1 in astrocytes and its impact on disease progression in amyotrophic lateral sclerosis (ALS). Using LoxSOD1G37R mice, which can be made to delete the mutant SOD1 gene specifically in astrocytes, the researchers found that reducing mutant SOD1 expression in astrocytes did not affect the onset of disease but significantly delayed microglial activation and slowed later disease progression. This suggests that mutant astrocytes are viable targets for therapies aimed at slowing the non-cell-autonomous killing of motor neurons in ALS. The findings also highlight the importance of astrocytes in modulating the inflammatory response through microglial activation, providing insights into potential therapeutic strategies.