Amyotrophic lateral sclerosis (ALS) has traditionally been described as a disease of motor neurons—the nerve cells that carry signals from the brain and spinal cord to muscles. As these cells deteriorate, patients progressively lose the ability to move, speak, swallow and breathe. New research from the Salk Institute for Biological Studies suggests that, at least in a widely used mouse model of ALS, another population of cells may actively accelerate this destruction. The study reports that microglia, the immune cells permanently stationed in the brain and spinal cord, use a molecular system known as TAM to identify and engulf living motor neurons. The discovery provides a new explanation for how inflammation in the nervous system may become destructive rather than protective, and could reshape the search for treatments aimed at slowing late-stage ALS.
ALS affects approximately 35,000 people in the United States, with thousands of new diagnoses each year. The disease can be caused by inherited mutations, although most cases are sporadic and arise without a clearly identifiable genetic trigger. Regardless of cause, the outcome is usually progressive loss of motor neurons in the brain and spinal cord. The resulting breakdown in communication between the nervous system and muscles produces weakness, twitching, impaired coordination and eventual paralysis. Existing treatments can modestly extend survival or slow progression for some patients, but none stops the underlying disease. Because motor neurons have received most of the attention, the role of neighboring support and immune cells has remained comparatively less understood.
Microglia are the central nervous system’s resident immune cells. They constantly survey their surroundings, remove damaged material and respond to infection or injury. Under normal conditions, this surveillance system is essential for maintaining healthy neural tissue. Microglia also remove dead cells through a process called phagocytosis, in which cellular debris is recognized, engulfed and digested. However, the same machinery that clears damaged cells can become harmful if it is activated inappropriately. The Salk team, led by Greg Lemke, focused on whether microglia might be using a natural cell-clearance pathway to eliminate motor neurons that were still alive in ALS-affected spinal cords.
The pathway at the center of the study is the TAM receptor system, a family of receptor tyrosine kinases consisting primarily of TYRO3, AXL and MERTK, commonly referred to as Mer. These receptors help immune cells recognize cells marked for removal. The system works through molecular bridges, including the proteins Gas6 and protein S, which bind to phosphatidylserine on a target cell’s surface and present it to TAM receptors. Phosphatidylserine is normally confined to the inner layer of the cell membrane, but it becomes exposed on the outside when a cell undergoes programmed cell death. This outward-facing phosphatidylserine acts as an “eat me” signal, allowing phagocytes to remove the dying cell without provoking excessive inflammation.
Lemke and colleagues examined SOD1 mice, a standard laboratory model carrying a mutant form of the human SOD1 gene associated with inherited ALS. In the spinal cords of these animals, the researchers found extensive evidence that microglia had engulfed motor neurons. They also observed increased levels of TAM proteins, particularly AXL and Mer, as the disease progressed. Detailed analysis indicated that motor neurons were displaying phosphatidylserine on their external membranes even though they had not yet died. This abnormal exposure effectively appeared to label living neurons as disposable, creating a molecular route through which activated microglia could attack them.
To test whether AXL and Mer were required for this process, the scientists bred ALS-model mice lacking both receptors. The result was unexpected. Removing the two TAM proteins caused the animals to become clinically sicker more rapidly, yet the mice survived longer. Examination of their spinal cords provided an explanation: the animals retained more motor neurons and preserved more of the neurons that control muscles, even though their overall disease symptoms initially appeared more severe. In mice with intact AXL and Mer signaling, microglia were filled with remnants of engulfed neurons. When the receptors were absent, this accumulation was markedly reduced, indicating that the TAM pathway was driving the inappropriate removal of motor neurons.
The finding does not mean that the TAM system is universally harmful. In healthy tissues, TAM receptors perform a vital housekeeping function by coordinating the clearance of billions of dead and dying cells. They also regulate immune responses and help prevent unnecessary inflammation. Completely disabling the pathway could therefore create serious problems elsewhere in the body. The Salk researchers emphasize that eliminating AXL and Mer is unlikely to be a straightforward treatment for ALS, particularly because the mouse experiments revealed a complicated relationship between neuronal preservation, motor symptoms and survival. Instead, the results point toward a more selective strategy: preventing the pathway from recognizing vulnerable but living neurons while preserving its normal role in tissue maintenance.
The study also raises questions about why ALS motor neurons expose phosphatidylserine prematurely. The abnormal signal could reflect stress caused by mutant SOD1, defects in membrane regulation, mitochondrial dysfunction or other molecular disturbances that occur during neurodegeneration. It is also unclear whether the same mechanism operates in people with sporadic ALS or in other forms of the disease. The mouse model reproduces important features of ALS but cannot capture the full genetic, cellular and clinical diversity of human illness. Further research will be needed to determine whether elevated AXL or Mer activity correlates with motor-neuron loss in patients, whether the receptors are activated at particular disease stages and whether their signaling can be modified without compromising essential immune functions.
The implications may extend beyond ALS. Activated microglia and elevated AXL have been observed in several neurodegenerative conditions, including Alzheimer’s disease, while related inflammatory and cell-clearance pathways have been implicated in Parkinson’s disease and other disorders. If living neurons in these diseases also acquire inappropriate “eat me” signals, microglial phagocytosis could represent a shared mechanism of damage. At the same time, the TAM system may offer an unusual opportunity for therapeutic engineering. Researchers in Japan and South Korea have developed TAM-based proteins that can deliberately label living cells for removal. In mouse studies, such molecules have been used to direct microglia toward B cells involved in lupus and toward cancer cells in melanoma. The same biology that may contribute to neuronal loss could therefore be adapted into a precision immunotherapy platform.
For ALS, however, the central message is caution as much as promise. Blocking TAM receptors alone would not address the upstream causes that make motor neurons vulnerable or cause phosphatidylserine to appear on their surfaces. A useful therapy may need to combine disease-specific interventions with carefully targeted modulation of microglial behavior, perhaps by interrupting the molecular bridge between phosphatidylserine and AXL or Mer rather than eliminating the receptors throughout the body. The Salk study offers a mechanistic link between neuronal stress, immune-cell activation and motor-neuron death, providing researchers with a new target for investigation. It also suggests that in neurodegeneration, the immune system’s most fundamental cleanup operation can become a weapon—one that may be stopped only by understanding precisely why healthy cells begin to look like cellular debris.
Subject of Research: Microglial use of TAM receptors to eliminate motor neurons in a mouse model of amyotrophic lateral sclerosis (ALS)
Article Title: Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis
News Publication Date: 20-Aug-2026
Web References: Salk Institute; https://www.salk.edu/scientist/greg-lemke/ ; Nature Communications article: https://www.nature.com/articles/s41467-026-76728-5
References: DOI: 10.1038/s41467-026-76728-5
Image Credits: Salk Institute
Keywords: Amyotrophic lateral sclerosis, ALS, motor neurons, microglia, TAM receptors, AXL, Mer, MERTK, neurodegeneration, neuroinflammation, SOD1, phosphatidylserine, phagocytosis, immunotherapy, neuroscience
Tags: ALSbrain immune cells in ALSimmune cell-mediated nerve cell destructioninflammation-induced neurodegenerationmicroglia in neurodegenerationmotor neuron degenerationmouse models of ALSnerve cell immune response mechanismsneuroinflammation in ALSpotential ALS treatments targeting immune cellsrole of microglia in ALS progressionTAM molecular system in microglia
