Toxic Factor Linked to ALS Neuron Death

NEW YORK, April 25 -- Glial cells -- long thought to be passive onlookers as motor neurons die in amyotrophic lateral sclerosis -- are actually major players, according to two research groups.

In companion papers published online in Nature Neuroscience, scientists at Columbia here and at Harvard reported that in ALS glial cells can secrete a toxic factor that selectively kills motor neurons.

The findings hold the promise of earlier diagnosis of the disorder -- also known as Lou Gehrig's Disease -- and may also open the door to possible therapeutic approaches, the researchers said.

"It was previously thought that astrocytes (the most abundant form of glial cell) were merely spectators watching their neighboring motor neurons die," said Serge Przedborski, M.D., Ph.D., of Columbia.

Instead, he said, "they are major players. The astrocytes and their cellular environment are specifically causing motor neuron death" while sparing other forms of neuron.

Some cases of familial ALS are associated with mutations in the gene coding for the enzyme superoxide dismutase. In cell culture experiments, using mouse cells, both research groups showed that:

• When grown together with mutated glial cells, motor neurons died whether or not they themselves expressed the superoxide dismutase mutation.
• Other types of neurons -- such as primary spinal GABAergic neurons -- were not affected when grown with mutated glial cells.

Dr. Przedborski and colleagues also reported that astrocytes are the only glial cells with the toxic effect. Fibroblasts, microglia, cortical neurons and myocytes expressing mutated superoxide dismutase "do not cause overt neurotoxicity," they reported.

Motor neurons expressing mutated forms of superoxide dismutase have structural changes, both groups reported -- they are smaller and have fewer long axons than wild-type neurons.

However, the Columbia group found that mutated motor neurons have a normal lifespan, in the absence of glial cells, while the Harvard group found they died more quickly than wild-type neurons.

The difference may come from the two groups using different sources for their cells or from some other quirk of the experimental design, said Kevin Eggan, Ph.D., who led the Harvard group.

The Columbia team also concluded that mutated glial cells secrete a toxic compound that selectively targets motor neurons through the so-called Bax cell death pathway.

When the mutated glial cells were grown with motor neurons in the presence of a compound -- the membrane-permeant pentapeptide VPMLK -- that blocks the Bax pathway, the researchers found that fewer neurons died.

Exactly what toxic factor activates the Bax pathway has not been determined, Dr. Przedborski said.

But if the cell culture experiments reflect what's actually happening in people with ALS, he said, "blocking the toxic factor released by astrocytes as early as possible could become an effective neuroprotective strategy against this disease."

He added that the findings may lead to earlier diagnosis. "Currently, we diagnose ALS at a point when a large number of motor neurons are already gone," he said.

But knowing what toxic factors are being released would open the possibility of being able "to screen people for elevated levels of these proteins and intervene in a tangible way perhaps even before a person displays any clinical sign of ALS," he said.

Dr. Eggan said in a statement that the studies are significant for another reason: they offer new ways of studying ALS.

"They provide a proof of concept," he said. "If you have embryonic stem cells that carry the genes for a disease -- in this case ALS -- you can make limitless quantities of the cells affected by the disease (and) study the disease process."