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

In a groundbreaking study spearheaded by Dr. Kazuhide Asakawa at the National Institute of Genetics in Japan, researchers have harnessed the power of single-cell–resolution imaging within transparent zebrafish models to probe the cellular mechanisms behind motor neuron vulnerability in ALS. This innovative approach allowed them to observe, in unprecedented detail, the physiological status and stress responses of individual spinal motor neurons in a living organism, linking structural properties with cellular dynamics.

The team’s observations reveal that large spinal motor neurons, tasked with generating powerful body movements and notably susceptible in ALS pathology, endure an inherent and continuous burden related to protein and organelle degradation. These neurons consistently exhibit elevated basal activity in three critical cellular pathways: autophagy, proteasome-mediated degradation, and the unfolded protein response. Together, these mechanisms constitute the cell’s principal modalities for maintaining protein and organelle quality control, suggesting that large motor neurons are persistently engaged in managing extensive proteostatic stress.

Autophagy involves the sequestration and lysosomal breakdown of damaged organelles and misfolded proteins, while proteasome activity facilitates the degradation of ubiquitinated proteins that could otherwise aggregate and impair cellular function. The unfolded protein response is triggered by endoplasmic reticulum (ER) stress, initiating a molecular reaction aimed at restoring proper protein folding. Elevated baseline activity in these systems points to a metabolic state where motor neurons operate near their degradation capacity limits under normal physiological conditions.

Intertwined with this intrinsic stress profile is the role of TDP-43, a DNA/RNA-binding protein that has emerged as a pivotal player in ALS pathology. Functional impairment or loss of TDP-43 protein dramatically exacerbates the degradation burden. The researchers found that early-phase acceleration of protein and organelle turnover — induced by TDP-43 dysfunction — initially supports axonal growth and neuronal plasticity, indicating a compensatory cellular response aimed at maintaining motor neuron function under stress.

However, this adaptive response is a double-edged sword. Over time, persistent hyperactivation of degradation pathways overwhelms cellular homeostasis, accelerating pathological processes that culminate in selective neuronal degeneration. This exhaustion model sheds light on why considerable proteostatic strain precedes motor neuron loss, aligning with clinical observations of progressive functional decline in ALS patients.

Dr. Asakawa explains, “The sheer size and elevated metabolic demand of these large motor neurons impose a relentless degradation workload. Our findings help explain why these cells are predisposed to early degeneration in ALS, highlighting the degradation burden as a potential therapeutic target.” This insight opens the door to strategies aiming to mitigate proteostatic stress — for instance, by modulating autophagy or proteasomal activity — as a promising avenue for future ALS interventions.

This work not only clarifies the cellular basis for ALS motor neuron selectivity but also enriches the broader landscape of neurodegenerative disease research, in which protein quality control dysfunction is a recurring theme. By pinpointing the intrinsic vulnerabilities of neuron subtypes based on their biological and morphological characteristics, the study offers a refined framework for understanding and potentially delaying neurodegeneration.

Further, the use of transparent zebrafish as a vertebrate model for real-time, single-cell analysis underscores the transformative potential of advanced imaging techniques in neuroscience. The capacity to visualize protein degradation dynamics within living neurons may catalyze discoveries across multiple neurodegenerative disorders characterized by proteostasis imbalance.

The findings prompt a reconsideration of how cellular stress responses are managed within large neurons and their correlation with disease onset and progression. Increased baseline degradation activity suggests a perpetual cellular attempt to counteract accumulating proteotoxic stress but also reveals the thin margin between adaptation and failure. Understanding where this threshold lies in motor neurons could be critical to developing interventions that preserve neuron integrity before irreversible damage ensues.

This study enriches ALS research by linking the cell biology of motor neurons to their unique pathological trajectory. The interplay of cell size, metabolic demands, and stress-response pathways outlines a mechanistic narrative explaining why these neurons succumb preferentially. Moreover, the identification of TDP-43’s role in magnifying intrinsic degradation stress consolidates its status as a central molecular culprit, encouraging further research into ways to protect or restore its function.

By elucidating these complex cellular relationships, Dr. Asakawa and colleagues provide a compelling explanation for long-standing clinical observations and experimental findings. Their work offers a beacon of hope for future therapeutic development, suggesting that reducing the proteostatic load on vulnerable neurons might slow, halt, or even reverse the relentless march of ALS.

In summary, the discovery that large spinal motor neurons naturally operate under heightened degradation demands—and that the loss of TDP-43 exacerbates this stress culminating in cell death—represents a pivotal advancement in ALS pathophysiology. This study not only solves key pieces of the ALS puzzle but also sets a foundation for innovative neuroprotective therapies that target intrinsic cellular liabilities before disease manifestation becomes irreversible.

Subject of Research: Cellular mechanisms underlying selective motor neuron vulnerability in amyotrophic lateral sclerosis (ALS) through proteostasis and degradation burden analysis.

Article Title: [Not explicitly provided in source content]

News Publication Date: [Not explicitly provided in source content]

Web References:

• National Institute of Genetics: https://www.nig.ac.jp/nig/
• Research Organization of Information and Systems (ROIS): https://www.rois.ac.jp/en/index.html
• DOI link to original paper: http://dx.doi.org/10.1038/s41467-025-65097-0

Image Credits: Kazuhide Asakawa, National Institute of Genetics

Keywords: amyotrophic lateral sclerosis, ALS, motor neurons, proteostasis, protein degradation, autophagy, proteasome, unfolded protein response, TDP-43, neurodegeneration, zebrafish model, neurobiology