Astrocytes play a critical role in determining the progression of inherited amyotrophic lateral sclerosis (ALS). The study shows that reducing mutant SOD1 expression in astrocytes delays disease progression but does not affect the onset of the disease. This suggests that mutant astrocytes are viable targets for therapies aimed at slowing the non-cell-autonomous death of motor neurons in ALS. ALS is an adult-onset neurodegenerative disease characterized by the progressive loss of motor neurons. Dominant mutations in the SOD1 gene are the most common cause of inherited ALS. Mutant SOD1 causes progressive motor neuron degeneration in rodents. While the exact mechanism of motor neuron death in ALS is unclear, evidence suggests that non-neuronal cells, such as astrocytes and microglia, play an active role in the disease process. Using a mouse model with a deletable SOD1 mutant gene, the study found that reducing mutant SOD1 in astrocytes delayed the progression of the disease but not its onset. This was achieved by using Cre recombinase to delete the mutant SOD1 gene in astrocytes. The study also showed that reducing mutant SOD1 in astrocytes inhibited microglial activation, which is a key factor in disease progression. The study also found that astrocytic and microglial activation are features of SOD1 mutant-mediated ALS. The presence of elevated GFAP-positive astrocytes before disease onset indicates astrogliosis, which is a progressive process. Despite the reduction of mutant SOD1 in astrocytes, astrogliosis was not significantly different between the two groups. Microglial activation was delayed in mice with reduced mutant SOD1 in astrocytes. This delay was associated with a reduction in the number of astrocytes with reduced mutant SOD1 and an increase in activated microglia. The study also found that nitric oxide production by microglia is increased in SOD1 mutant mice, and this production is inhibited when mutant SOD1 is reduced in astrocytes. The study highlights the role of astrocytes in inherited ALS, showing that they can produce and release components that accelerate motor neuron death. The study also shows that the loss of the EAAT2 glutamate transporter in astrocytes can lead to glutamate-dependent excitotoxicity, a component of the disease. However, the reduction of mutant SOD1 in astrocytes did not affect the loss of EAAT2, indicating that the damage is non-cell autonomous. The study concludes that mutant SOD1 in astrocytes determines the timing of microglial activation and infiltration, which can lead to further damage to motor neurons through an inflammatory response. These findings support the development of therapies targeting astrocytes to slow disease progression in ALS.Astrocytes play a critical role in determining the progression of inherited amyotrophic lateral sclerosis (ALS). The study shows that reducing mutant SOD1 expression in astrocytes delays disease progression but does not affect the onset of the disease. This suggests that mutant astrocytes are viable targets for therapies aimed at slowing the non-cell-autonomous death of motor neurons in ALS. ALS is an adult-onset neurodegenerative disease characterized by the progressive loss of motor neurons. Dominant mutations in the SOD1 gene are the most common cause of inherited ALS. Mutant SOD1 causes progressive motor neuron degeneration in rodents. While the exact mechanism of motor neuron death in ALS is unclear, evidence suggests that non-neuronal cells, such as astrocytes and microglia, play an active role in the disease process. Using a mouse model with a deletable SOD1 mutant gene, the study found that reducing mutant SOD1 in astrocytes delayed the progression of the disease but not its onset. This was achieved by using Cre recombinase to delete the mutant SOD1 gene in astrocytes. The study also showed that reducing mutant SOD1 in astrocytes inhibited microglial activation, which is a key factor in disease progression. The study also found that astrocytic and microglial activation are features of SOD1 mutant-mediated ALS. The presence of elevated GFAP-positive astrocytes before disease onset indicates astrogliosis, which is a progressive process. Despite the reduction of mutant SOD1 in astrocytes, astrogliosis was not significantly different between the two groups. Microglial activation was delayed in mice with reduced mutant SOD1 in astrocytes. This delay was associated with a reduction in the number of astrocytes with reduced mutant SOD1 and an increase in activated microglia. The study also found that nitric oxide production by microglia is increased in SOD1 mutant mice, and this production is inhibited when mutant SOD1 is reduced in astrocytes. The study highlights the role of astrocytes in inherited ALS, showing that they can produce and release components that accelerate motor neuron death. The study also shows that the loss of the EAAT2 glutamate transporter in astrocytes can lead to glutamate-dependent excitotoxicity, a component of the disease. However, the reduction of mutant SOD1 in astrocytes did not affect the loss of EAAT2, indicating that the damage is non-cell autonomous. The study concludes that mutant SOD1 in astrocytes determines the timing of microglial activation and infiltration, which can lead to further damage to motor neurons through an inflammatory response. These findings support the development of therapies targeting astrocytes to slow disease progression in ALS.