MERKT is Involved in Enabling Microglia to Kill Motor Neurons in ALS
Amyotrophic lateral sclerosis (ALS) is characterized by the loss of motor neurons. Aggregation of TDP-43 is thought to be involved in producing cell death in the brain. Here researchers present evidence in a mouse model of ALS for microglia to destroy motor neurons, and identify key cell surface features that enable this activity. Whether the model is good and this will also be the case in human tissues is the usual question when considering mouse models of neurodegenerative conditions. These models tend to embody assumptions about the cause of disease, using genetic and other techniques to force the existence of specific mechanisms, as mice normally do not develop the feature of brain aging found in humans. Thus one can end up with an artificial mouse condition that resembles the natural human condition, but is not the same in important aspects.
Activation of microglia is a prominent feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that leads to the death of motor neurons. A key component of this activation is elevated expression of the TAM receptor tyrosine kinases Axl and Mer (gene name Mertk). Here we show that germline and microglial-restricted inactivation of the Axl and Mertk genes in the SOD1G93A mouse model of ALS leads to an extension of lifespan, which is tied to the preservation of cholinergic motor neurons and neuromuscular synapses.
Also elevated on SOD1G93A neuronal surfaces is the essential TAM co-ligand phosphatidylserine, a potent 'eat-me' signal through which apoptotic cells are engulfed by microglia. Correspondingly, we find that microglial lysosomes are filled with the remains of cholinergic neurons in the SOD1G93A spinal cord, whereas this accumulation is markedly reduced in the SOD1G93A cord when Axl and Merkt are deleted. Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS.