Location Matters for Motoneurons

The quality of neighborhood that motor neurons find themselves in determines whether they remain healthy or degenerate, new research shows. The motor neurons' own inherited vigor isn't as important. The results reveal new ways to approach therapies for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

ALS is a neurodegenerative disorder in which people lose control of their muscles, which ultimately atrophy. Researchers believe that the muscles wither after the motor neurons that innervate them die. Although the majority of ALS cases arise spontaneously, about 2% are due to inherited mutations in the gene for superoxide dismutase (SOD1), an enzyme that cleans up cell-damaging free radicals. When the mutant SOD1 gene is overproduced in mice, the animals suffer progressive neurodegeneration similar to ALS.

Scientists have long thought that the mutant SOD1 somehow mucks up the inner workings of the motor neurons and kills them, but no one had been able to prove it. Last year, a research group overexpressed the mutant SOD1 in mice--only in motor neurons--but the mice showed no ill effects. To follow up, another team, led by Don Cleveland at the University of California, San Diego, engineered mice with some normal cells and some cells with a mutant SOD1 gene to investigate whether mutant neighboring cells contribute to neurodegeneration.

The researchers found that the only time that motor neurons degenerated was when they were surrounded by mutant helper cells. The higher the percentage of sick helper cells, they report in the 3 October issue of Science, the worse the neurodegeneration and the worse the animals' disease. In contrast, when healthy helper cells surrounded SOD1-containing motor neurons, the neurons didn't die--and the animals lived a normal life span. The researchers were unable to pinpoint what types of helper cells were the most important, but those experiments are in progress.

The work should cause a "mindset change for neurodegenerative diseases," because the focus has always been on the nerve cells themselves, says neuroscientist Jeffrey Rothstein of Johns Hopkins University School of Medicine. "It's equally important to consider nonneuronal cells." Neighboring cells could be targeted by stem cell therapies that seek to replace cells with the mutation, or by drug therapies to correct the defect. He says the role of the neighboring cells is surprising: "I never presumed they would be this important."

Related sites
Don Cleveland's site
Information about ALS from NIH