LA JOLLA (August 20, 2026)—Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that, according to the CDC, currently impacts around 35,000 Americans—with 5,000 more diagnosed each year. Risk climbs with age, and treatments only slow progression. With no cure and an aging population, scientists are urgently seeking insights that could change those devastating outcomes.
The search for a cure has long focused on movement-controlling nerve cells, or motor neurons, which are progressively lost throughout the disease course to cause ALS's characteristic muscle and nerve degeneration. But another type of nervous system cell—the resident immune cells in the brain and spinal cord, called microglia—is stepping up to the lab bench.
New Salk Institute research shows a novel way that microglia contribute to ALS progression and death. Microglia use TAM receptors—a class of proteins that facilitate cell destruction and were discovered by senior author Greg Lemke, PhD —to find and kill motor neurons in the spinal cords of mice with ALS.
The study was published in Nature Communications on August 15, 2026.
Why focus on microglia?
ALS is a progressive disease that gradually destroys nerve cells. Motor neurons that normally transmit information from the brain to the body's muscles begin to fail and disappear, creating a growing rift between the brain and body. What starts as tremors and incoordination soon grows into an inability to walk, talk, eat, and, eventually, breathe.
Neurons are often the center of attention in brain and neurodegeneration research, but other cells in the central nervous system are important, too. Recent studies have shown microglia, which are immune cells specific to the brain and spinal cord, are very active during human ALS. The question is: Why?
Active microglia can be easily identified in research by assessing their expression of TAM receptors. Lemke discovered this family of proteins, which are critical bridges between the immune system and the rest of the body, more than three decades ago.
"Cells that are dying throw an 'eat me' sign out on their surface, and the TAM system recognizes that sign," explains Lemke, distinguished professor emeritus at Salk. "It's an essential system that clears billions upon billions of dead and dying cells from the body daily. We wondered whether microglia were corrupting this TAM system to kill living neurons in ALS."
Is the TAM system to blame?
To determine whether the TAM system was the link between microglia activation and motor neuron death in ALS, the Salk researchers started with the most widely used mouse model of ALS, called SOD1. These mice express a mutant SOD1 protein that causes ALS in people.
They first found that many motor neurons had been eaten in the spinal cords of SOD1 mice. The levels of TAM proteins were also elevated in these mice, particularly Axl and Mer. Looking closer at the motor neurons, the scientists noticed those "eat me" signs, which are little molecules called phosphatidylserine, were being displayed on cells when they shouldn't be. From there, the TAM system springs into action, guiding microglia to their next meal: a live neuron.
The natural next question in the lab, Lemke shares, is "what happens when we eliminate Axl and Mer?" Without these two TAM family proteins, the mice got sicker faster but lived longer. "This was very weird to see," continues Lemke. "Since the TAM system is so important throughout the body, you would assume that removing them would be devastating."
"But it somehow was not devastating," says first author Youtong Huang, PhD, a former graduate student researcher in Lemke's lab. "When we looked at how many motor neurons mice without Axl and Mer had, compared to mice with Axl and Mer, we found losing the TAM proteins meant preserving muscle controls."
Microglia in SOD1 spinal cords were stuffed with eaten neurons, but not when the TAM system was disabled. This accumulation of microglia-eaten neurons was markedly reduced without TAM proteins in play.
"The bottom line is, microglia are using the TAM system to eat cells that aren't dead," says Lemke. This is the first time the TAM system has been shown to target living cells—a finding that likely has repercussions in other parts of the body beyond the central nervous system.
What does this mean for ALS and neurodegeneration research?
The study identifies a novel mechanism to help explain why microglial activation is linked to ALS and how this activation contributes to disease progression and lethality.
"But it's important to note that, while these findings may suggest we start designing therapies that remove the TAM system, there are so many more variables at play, and we really don't see that as the best option," says Huang. "Rather, 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."
The fundamental insights into the TAM system, microglia, and neuronal biology exposed by the paper will be of great use in neurodegeneration research beyond just ALS. Other neurodegenerative diseases bear similar markers to ALS—for example, elevated Axl is a hallmark of Alzheimer's.
The study also adds a significant discovery to the worlds of molecular biology and immunology. As the study ran its course, the authors recognized a new opportunity to optimize immunotherapies using the TAM system. Once they knew that the TAM system could kill living cells, groups in Japan and Korea discovered a way to activate the TAM family of proteins to tag any living cell of interest and recruit microglia to gobble them up.
"Jun Suzuki's research group in Kyoto engineered a TAM-based protein that was able to induce 'eating' of live B cells to alleviate autoimmunity in mice with lupus, then engineered another TAM-based protein that enabled 'eating' of live cancer cells and reduced tumor growth in mice with melanoma," shares Huang.
"There is enormous potential for this in clinical translation," says Lemke. "Rather than engineering entire cells as immunotherapies—a process that is far more complicated, time-consuming, and invasive—we could simply design TAM-based proteins that target any cell you'd like. I'm really excited to see where this discovery goes and how it changes immunotherapy opportunities."
Other authors and funding
Other authors include Ananya Mavinkurve, Bristy Sabikunnahar, and Beth Stevens of Boston Children's Hospital and the Broad Institute.
The work was supported by the National Institutes of Health (RF1 AG060748, R01 AI101400, RF1 NS092578), Harvard Medical School, Salk Women in Science Award, UC San Diego, Marguerite Vogt, and H. A. and Mary K. Chapman Charitable Trust.
This press release was written by Isabella Davis.
About the Salk Institute for Biological Studies
The Salk Institute is an independent, nonprofit research institute founded in 1960 by Jonas Salk, developer of the first safe and effective polio vaccine. The Institute's mission is to drive foundational, collaborative, risk-taking research that addresses society's most pressing challenges, including cancer, Alzheimer's, and agricultural vulnerability. This foundational science underpins all translational efforts, generating insights that enable new medicines and innovations worldwide. Learn more at www.salk.edu .
