In two strains of mice with SOD1 mutations, the brain teems with microglia from the bone marrow (yellow).

Immune cells fight a losing battle against a harmful abnormal protein found in some cases of amyotrophic lateral sclerosis (ALS), as Kang and Rivest report. The findings support the hypothesis that extracellular accumulations of faulty proteins trigger the disease's neural damage.

Researchers aren't sure why muscle-controlling motor neurons deteriorate in ALS. Patients with the inherited form of the disease carry mutations in the gene for the antioxidant enzyme SOD1. But how defective SOD1 causes neurodegeneration remains uncertain. One possibility is that the altered SOD1 builds up outside neurons and eventually kills them. Several studies suggest that some neighboring cells can shield neurons from the protein's ill effects. Kang and Rivest tested whether microglia, the main infection-combating cells in the brain, were protective.

The researchers transplanted bone marrow with labeled cells into two mouse strains that manufacture different forms of mutant human SOD1. In both strains, the cells swarmed from the marrow to the brain, presumably to attack the SOD1. Injecting defective SOD1 into the brains of normal animals also drew a crowd of microglia. The team found that SOD1 activated microglia, but not if the cells lacked an adapter protein called MyD88.

To probe MyD88's role, the researchers implanted bone marrow lacking the protein into mice from the two strains. In one strain, MyD88-deficiency caused the animals to develop symptoms sooner and to die nearly two months earlier. In the other stain, however, losing MyD88 signaling had no effect on survival. It's possible that the SOD1 variant in this strain kills the animals so quickly that the transplants didn't have time to help.

The study suggests that microglia from the bone marrow protect neurons from toxic buildups of mutant SOD1. But if microglia are on the job, why do the animals still die? The researchers hypothesize that, although microglia can keep faulty SOD1 in check temporarily, the immune system eventually tires, allowing lethal amounts of the protein to accumulate.


Kang, J., and S. Rivest.
J. Cell Biol.