Immune Cells Caught Eating Living Neurons in ALS, Salk Study Finds

In amyotrophic lateral sclerosis (ALS), the nerve cells that carry signals from the brain to the muscles, called motor neurons, gradually die, breaking the connection between brain and body. Salk Institute researchers have now identified another contributor to that damage: immune cells in the spinal cord, called microglia, that use a cellular cleanup system to target and consume motor neurons that are still alive. The study was published in Nature Communications. ALS currently affects around 35,000 Americans, according to the CDC, with another 5,000 diagnosed each year; existing treatments can only slow the disease, and there is no cure.

The cleanup system relies on a family of proteins called TAM receptors that helps the body recognize and remove dying cells by detecting an “eat me” signal, called phosphatidylserine, that dying cells display on their surface. Senior author Greg Lemke, who discovered the TAM receptor family more than three decades ago, wanted to know whether microglia were corrupting this system in ALS. Using SOD1 mice, the standard mouse model of ALS, the team found motor neurons wrongly displaying the “eat me” signal while still alive, along with elevated levels of two TAM proteins, Axl and Mer, in the spinal cord.

When the researchers removed Axl and Mer from the mice, the animals became sick more quickly but survived longer, and their spinal cords retained more motor neurons than mice with the TAM proteins intact. “The bottom line is, microglia are using the TAM system to eat cells that aren’t dead,” Lemke said. It is the first time the TAM system has been shown to target living cells rather than dying ones.

First author Youtong Huang cautioned against simply designing therapies that remove the TAM system altogether, saying there are many other variables at play. “Therapies that target the TAM system must also target the underlying mechanisms of ALS—or other neurodegenerative diseases like Alzheimer’s or Parkinson’s—to be truly effective,” Huang said.