Toxic Neighbors Kill Nerve Cells In Genetic ALS

Nervous system “support” cells known as glia (glue) may play a big role in whether spinal cord nerve cells live or die in people with amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), say researchers supported by the Muscular Dystrophy Association (MDA) at Columbia University in New York and investigators at Harvard University in Cambridge, Mass.

In one set of experiments, MDA research grantee Serge Przedborski at Columbia and colleagues, who published their findings online April 15 in Nature Neuroscience, demonstrated that a type of ALS-affected glia, called astrocytes, secrete an unknown toxic compound that kills healthy motor neurons, the muscle-controlling nerve cells affected in this disease.

The astrocytes became toxic when they were given a mutated version of a gene known as SOD1, which is known to cause a genetic form of ALS in humans and mice. (About 2 percent of human ALS cases are caused by mutated SOD1 genes.)

Although it’s been previously shown that various cells in the “neighborhood” of the motor neurons can influence their survival for better or worse, this is the first time such a specific effect on motor neuron survival has been identified.

Another set of experiments, conducted by Kevin Eggan at Harvard and colleagues, and also published online April 15 in Nature Neuroscience, yielded similar results.

This group found that astrocytes carrying mutated SOD1 genes reduced the survival rate of both normal motor neurons and those that themselves carried mutated SOD1 genes, but the reduction in survival was significantly greater if the motor neurons also had the mutated genes, as they would in people with genetic ALS.

Taken together, these findings lead to “good news, bad news” conclusions for ALS research. The good news is that transplanting stem cells that become astrocytes instead of motor neurons might have a significant beneficial effect by providing neurons with a more supportive environment.

Astrocytes are easier to grow in the lab and don’t have to make the complex connections with other cells that motor neurons have to make, so deriving them from stem cells and transplanting them would almost certainly be easier than deriving and transplanting motor neurons.

The bad news is that, if stem cells destined to become motor neurons were transplanted into a spinal cord harboring abnormal astrocytes, they probably wouldn’t survive long.

The extent to which these findings apply to ALS that isn’t caused by a mutated SOD1 gene isn’t yet clear, but experts in the field generally believe that the biological underpinnings of SOD1-related and non-SOD1-related ALS are similar.