Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis

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 SOD1^G93A 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 SOD1^G93A 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 SOD1^G93A spinal cord, whereas this accumulation is markedly reduced in the SOD1^G93AAxl^-/-Mertk^-/- cord. Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS.