New details about how motor neurons die in ALS have been uncovered by a new cell-culture system that combines spinal cord or brain cells from ALS patients with human motor neurons. The culture system shows that patient astrocytes (shown here with a blue-stained nucleus) release a toxin that kills motor neurons via a recently discovered process described as a controlled cellular explosion. Image: Diane Re.

NEW YORK, NY (February 6, 2014) In most cases of amyotrophic lateral sclerosis (ALS), or Lou Gehrigs disease, a toxin released by cells that normally nurture neurons in the brain and spinal cord can trigger loss of the nerve cells affected in the disease, Columbia researchers reported today in the online edition of the journal Neuron.

The toxin is produced by star-shaped cells called astrocytes and kills nearby motor neurons. In ALS, the death of motor neurons causes a loss of control over muscles required for movement, breathing, and swallowing. Paralysis and death usually occur within 3 years of the appearance of first symptoms.

The report follows the researchers previous study, which found similar results in mice with a rare, genetic form of the disease, as well as in a separate study from another group that used astrocytes derived from patient neural progenitor cells. The current study shows that the toxins are also present in astrocytes taken directly from ALS patients.

I think this is probably the best evidence we can get that what we see in mouse models of the disease is also happening in human patients, said the studys senior author, Serge Przedborski, MD, PhD, the Page and William Black Professor of Neurology (in Pathology and Cell Biology), Vice Chair for Research in the department of Neurology, and co-director of Columbias Motor Neuron Center.

The findings also are significant because they apply to the most common form of ALS, which affects about 90 percent of patients. Scientists do not know why ALS develops in these patients; the other 10 percent of patients carry one of 27 genes known to cause the disease.

Now that we know that the toxin is common to most patients, it gives us an impetus to track down this factor and learn how it kills the motor neurons, Dr. Przedborski said. Its identification has the potential to reveal new ways to slow down or stop the destruction of the motor neurons.

In the study, Dr. Przedborski and study co-authors Diane Re, PhD, and Virginia Le Verche, PhD, associate research scientists, removed astrocytes from the brain and spinal cords of six ALS patients shortly after death and placed the cells in petri dishes next to healthy motor neurons. Because motor neurons cannot be removed from human subjects, they had been generated from human embryonic stem cells in the Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, also at CUMC.

Within two weeks, many of the motor neurons had shrunk and their cell membranes had disintegrated; about half of the motor neurons in the dish had died. Astrocytes removed from people who died from causes other than ALS had no effect on the motor neurons. Nor did other types of cells taken from ALS patients.

Astrocytes from ALS patients release a toxin that kills human motor neurons. Left: a disintegrating motor neuron on top of human astrocytes (blue). Right: a healthy motor neuron on top of astrocytes from people unaffected by ALS. Image: Diane Re.

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