When cells recognize danger, like an infection, immune molecules are activated to sound an alarm that recruits and activates immune cells to the site of damage to try to eliminate it and orchestrate tissue repair. Sometimes, the immune response involves a family of proteins called gasdermins, which trigger cells to die through a highly inflammatory process called pyroptosis. One type of gasdermin, gasdermin E, is expressed in the brain most highly in nerve cells. But no one knew what it’s doing.
The research team, led by Dr. Lieberman and Chiu, first examined how gasdermin E affects neurons. The team developed models of neurons from mice and from human samples and looked at the effects of gasdermin E on axons, or the parts of neurons that send electrical signals. The researchers found that when neurons detect a hazard, gasdermin E drives damage to the powerhouse of the cell, known as mitochondria, and the axons. The axons degenerate, but the cells don’t die.
“If you look at a plate of neurons, you see a jungle of axons. But if you look at a plate where gasdermin E is activated, you see retractions of these cellular processes,” explains Himanish Basu, a postdoctoral researcher in Chiu’s lab at Harvard University who led this study. This retraction happens in nerves in the muscles of patients with ALS, a progressive disease characterized by muscle twitching and weakness, but eventually progressing to muscle atrophy and paralysis.
“Our study is an example of how immunology can help explain neurodegeneration on a mechanistic level, and what drives axon loss and neuronal injury,” says Dylan Neel, an MD/PhD student in Chiu’s lab who co-led this study.
