Glial cells contribute to motor neuron death in amyotrophic lateral sclerosis (ALS), but the mechanisms by which they do so have been unclear. Now, Ashley Frakes and her colleagues identify inflammatory nuclear factor-kB (NF-κB) signaling in microglia as a driver for motor neuron death and disease progression in mouse models of ALS (Neuron 81, 1009–1023, 2014 ).

NF-κB activation is known to occur in glia in individuals with ALS, and the researchers found that this was also the case within the microglia of mice with mutations in superoxide dismutase (SOD) that cause ALS in humans. Inhibiting NF-κB by genetic ablation of its activator in astroglia did not reduce neuron death in the mice, but inhibiting NF-κB in microglia did protect neurons and extended the lifespan of the mice. Activating NF-κB in microglia in wild-type mice led to motor neuron death, probably owing to conversion of the microglia to a proinflammatory phenotype.

Credit: Nancy Kedersha / UCLA / Science Source

The findings suggest that targeting NF-κB signaling in microglia could be a potential therapeutic approach to slow ALS pathogenesis.