Are predatory brain immune cells eating nerve cells in Amyotrophic lateral sclerosis (ALS)?

Good news!

"Highlights

• Salk scientists discover that central nervous system-resident immune cells called microglia use TAM receptors (discovered by study senior author Greg Lemke in 1991) to eat specific nerve cells in mouse model of ALS
• The study is the first to show TAM receptors can be used to kill living nerve cells
• The insights contribute to ongoing efforts to harness TAM receptors in clinical settings to treat cancers, autoimmune disorders, and more

...

Neurons are often the center of attention in brain and neurodegeneration research, but other cells in the central nervous system are important, too. Recent studies have shown microglia, which are immune cells specific to the brain and spinal cord, are very active during human ALS. The question is: Why? ...

Active microglia can be easily identified in research by assessing their expression of TAM receptors. ... discovered this family of proteins, which are critical bridges between the immune system and the rest of the body, more than three decades ago. ...

To determine whether the TAM system was the link between microglia activation and motor neuron death in ALS, the ... researchers started with the most widely used mouse model of ALS, called SOD1. These mice express a mutant SOD1 protein that causes ALS in people.

They first found that many motor neurons had been eaten in the spinal cords of SOD1 mice. The levels of TAM proteins were also elevated in these mice, particularly Axl and Mer.

Looking closer at the motor neurons, the scientists noticed those “eat me” signs, which are little molecules called phosphatidylserine, were being displayed on cells when they shouldn’t be. From there, the TAM system springs into action, guiding microglia to their next meal: a live neuron.

The natural next question ... is “what happens when we eliminate Axl and Mer?” Without these two TAM family proteins, the mice got sicker faster but lived longer. ...

“When we looked at how many motor neurons mice without Axl and Mer had, compared to mice with Axl and Mer, we found losing the TAM proteins meant preserving muscle controls.” ..."

From the abstract:

"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 SOD1G93AAxl-/-Mertk-/- cord.

Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS."

Are predatory brain immune cells eating nerve cells in ALS? – Salk Institute "Salk Institute scientists discover central nervous system immune cells find and kill specific nerve cells in the spinal cords of mice with late-stage ALS, exacerbating the condition; findings could be harnessed in cancer and autoimmune therapy innovation efforts"

Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis (open access, but still in press)

Microglia (green) contain the remnants of motor neurons (purple) inside microglial lysosomes (yellow).