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Support Cells Trigger Neuron Death in ALS

For release: Thursday, August 2, 2007

Star-shaped support cells in the brain secrete a toxin that kills motor neurons in a model of amyotrophic lateral sclerosis (ALS), two new studies show.  The studies may lead to new ways of diagnosing and treating the disorder.

“We all grew up with the idea that neuron degeneration is due to a problem in the neurons.  However, neurons are not alone in a desert.  They are surrounded by other cells,” says Serge Przedborski, M.D., Ph.D., of Columbia University Medical Center.  “This work shows that the other cells play a very significant role in the death of neurons.”  Dr. Przedborski’s study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

The studies suggest that treatments which modify the activity of the non-neuronal cells, called astrocytes, may be useful in treating human ALS, a fatal neurological disorder that affects about 20,000 people in the United States.  The new findings also suggest that treatments which replace neurons may fail unless the researchers can prevent the astrocyte-produced toxin from killing the transplanted cells.   

A hallmark of ALS is that it destroys only motor neurons, which control movement.  Neurons that control thinking, feeling, hearing, and other functions are usually unaffected.

To learn how astrocytes affect motor neurons in ALS, Dr. Przedborski and his colleagues cultured astrocytes with motor neurons.  Some of the neurons were taken from mouse spinal cords, while others were grown from mouse embryonic stem cells.  Some of the astrocytes and neurons had mutations in a gene called SOD1.  These mutations cause one form of human ALS.  Other neurons and astrocytes were normal. 

Motor neurons with SOD1 mutations were smaller and had shorter nerve fibers than normal, but when they were cultured with normal astrocytes, they lived as long as normal neurons.  When normal motor neurons were cultured with mutant astrocytes, they began to look stunted, and many of them died within days, the researchers found. 

Next, the researchers showed that the mutant astrocytes released a toxin that killed normal motor neurons even after the astrocytes were removed from the culture dish.  This toxin did not harm sensory neurons or any other cells.  Further experiments showed that the astrocyte-produced toxin worked by activating a protein called Bax, which triggers a process called programmed cell death.  Treating the cell cultures with a Bax inhibitor reduced the number of motor neurons that died.

A second study,led by Kevin Eggan, Ph.D., of Harvard University, also showed that astrocytes with SOD1 mutations kill embryonic stem cell-generated neurons in culture.  Both studies appear in the May 2007 issue of Nature Neuroscience. [1],[2]

“Beyond the novel findings presented in these studies, this work is a nice example of how embryonic stem cells can be utilized as an important tool to further our understanding of a disease process,” says David Owens, Ph.D., an NINDS program director for stem cell research.

While these studies clearly show that SOD1 mutated astrocytes can cause motor neuron death, there is no evidence yet that the same phenomenon happens in sporadic ALS, which is not linked to SOD1 mutations, Dr. Przedborski says.  He and his colleagues are planning new studies to test whether astrocytes kill neurons in sporadic ALS. 

"If indeed there is a toxic factor secreted by astrocytes in human ALS, it may be that we could use that factor to tell us about disease activity and prognosis," Dr. Przedborski says.  Tests for the astrocyte-produced toxin might be used to diagnose ALS in the early stages, he adds.  This could allow doctors to halt the disease before it causes significant damage.  Such tests also might provide a quick way to determine whether people are responding to drugs being tested in clinical trials.

The studies also suggest that drugs which interfere with or neutralize the toxin released by astrocytes could be useful in treating ALS.  "If you are dealing with a fire that starts inside the home, you call the fire department to extinguish it," Dr. Przedborski says.  "However, if the fire is coming from the outside, you can take steps to prevent it from reaching your home." 

The researchers are now studying animal models of ALS to learn how astrocytes affect motor neurons in living animals, which are much more complex than cells grown in culture dishes.  They also need to identify the toxin released by the astrocytes.  Eventually, they hope to use their cell culture system to test potential new drugs for ALS.

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system.  The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services.  It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit

-By Natalie Frazin

[1]Nagai M, Re DB, Nagata T, Chalazonitis A, Jessel TJ, Wichterle H, Przedborski S.  “Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons.”  Nature Neuroscience, May 2007, Vol. 10, No. 5, pp. 615-622.

[2]Di Giorgio FP, Carrasco M, Siao M, Maniatis T, Eggan K. "An embryonic stem cell based model for ALS: Non-cell autonomous affects of glial cells on motor neurons." Nature Neuroscience, May 2007, Vol. 10, No. 5, pp. 608-614.

Last Modified August 2, 2007