Mouse ALS Study Points to Mertk-Linked Microglial Killing of Motor Neurons

A study in a genetically engineered mouse model of amyotrophic lateral sclerosis (ALS) suggests that microglia may contribute directly to motor-neuron loss through the Axl and Mertk signaling system. Disabling those genes in the mice was associated with longer survival and preservation of some motor neurons and neuromuscular synapses.

The research focused on the SOD1G93A mouse model, which is used to study ALS-related neurodegeneration. In ALS, motor neurons—the nerve cells that control movement—die over time. Microglia, immune cells in the central nervous system, become activated during the disease. The researchers examined whether this activation could lead microglia to engulf motor neurons rather than merely respond to damage occurring around them.

Axl and Mer are TAM receptor tyrosine kinases, cell-surface receptors involved in the activation state of microglia. The Mer receptor is encoded by the Mertk gene. The study reported that both broad, inherited inactivation of Axl and Mertk and microglia-restricted inactivation of the genes extended lifespan in SOD1G93A mice. This effect was linked to preservation of cholinergic motor neurons and neuromuscular synapses.

The researchers also identified phosphatidylserine on the surfaces of neurons in the ALS mouse model. Phosphatidylserine can function as an “eat-me” signal, marking cells for engulfment by phagocytic immune cells. Consistent with that finding, microglial lysosomes in the spinal cords of the SOD1G93A mice contained remnants of cholinergic neurons. That accumulation was substantially lower when Axl and Mertk were deleted.

Taken together, the results support the researchers’ interpretation that microglia may phagocytically kill living neurons in this model, potentially accelerating disease progression. The findings identify a cellular pathway that could help explain how activated microglia are involved in motor-neuron loss, but they do not establish that the same process drives human ALS.

The study’s central limitation is the use of a mouse model. SOD1G93A mice are genetically engineered to develop an ALS-like condition, and such models can reflect specific assumptions about disease mechanisms. The source reporting notes that mice do not naturally develop the same form of brain aging seen in humans, meaning that an engineered condition can resemble human disease without reproducing all of its important biology. Whether the Axl-Mertk mechanism and microglial behavior observed here occur in human ALS tissue remains an open question.