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In Vivo


Toxins Released from Astrocytes
Found to Kill Motor Neurons in ALS


Photo: Charles Manley
ALS research team, from left: Diane B. Re, Alcmene Chalazonitis, Serge Przedborski, Tetsuya Nagata and Hynek Wichterle.
ALS research team, from left: Diane B. Re, Alcmene Chalazonitis, Serge Przedborski, Tetsuya Nagata and Hynek Wichterle.
Astrocytes, cells that usually nourish neurons, are responsible for the death of motor neurons in at least some cases of amyotrophic lateral sclerosis (ALS), according to a study led by Serge Przedborski, M.D., Ph.D., co-director of Columbia’s Center for Motor Neuron Biology and Disease.
   The findings represent a shift in knowledge about ALS, a fatal disease that affects about 30,000 people in the United States. People with ALS become increasingly paralyzed as their motor neurons, which control movement, degenerate over the course of the disease.
   Until now, scientists have not known which cells to blame for the deaths: the motor neurons themselves, neighboring cells, or a combination of both. The new research steers the blame to a toxin released by neighboring astrocytes. It was published in the May issue of Nature Neuroscience, alongside an independent Harvard study that found similar results.
   The new discovery may open new avenues for diagnosis and treatment.
   “If our experiments faithfully model the situation occurring in ALS patients, then we can envision that blocking the putative toxin produced by mutant astrocytes may be effective in slowing the progress of this disease,” says Dr. Przedborski, who is also Page and William Black Professor of Neurology and professor of pathology and cell biology. “The presence of an astrocytic toxin also suggests that embryonic stem cells once placed into an ALS spinal cord to replace lost motor neurons will be subjected to a deadly environment. Thus, optimal response to such repair procedures may have to involve concomitant administration of drugs capable of abating the astrocytic toxicity.”
   The researchers – including postdoctoral fellows Makiko Nagai, M.D., Ph.D., Diane Re, Ph.D., and Tetsuya Nagata, M.D., Ph.D. – and Alcmene Chalazonitis, Ph.D., senior research scientist in anatomy & cell biology, discovered the toxin in experiments with cells from mice with a rare form of ALS. In this form of ALS, the disease is caused by a mutation in the superoxide dismutase gene (SOD1), which is responsible for only a small percentage of cases in people, but is the sole known cause of the disease.
   To identify which cell causes motor neurons to die, the researchers mixed and matched ALS motor neurons and astrocytes with the same cells from normal mice. The ALS motor neurons thrived when paired with normal astrocytes, though they were slightly smaller than usual. Normal motor neurons, in contrast, died when paired with ALS astrocytes or with the ALS astrocyte’s culture medium.
   “It is like growing up in a bad neighborhood,” Dr. Przedborski says. “The ALS astrocytes create a bad neighborhood that has a negative influence on otherwise good neurons.”
   The neighborhood was just as bad for motor neurons derived from embryonic stem cells, the researchers discovered. When paired with toxic ALS astrocytes, about half of the embryonic stem cell-derived neurons died, matching the death rate of natural motor neurons.
   Without strategies to protect motor neurons from the toxin, new neurons introduced into a patient will most likely suffer the same fate as their natural predecessors.
   “There has, perhaps, been too much emphasis placed on using embryonic stem cells as replacements for cells killed by neurodegenerative diseases,” says co-author Hynek Wichterle, Ph.D., assistant professor of pathology, who developed the technique used to coax embryonic stem cells into motor neurons. “Because embryonic stem cell derived motor neurons can be generated in large quantities they will initially serve as a useful tool to identify the toxin produced by astrocytes and to discover new drugs that can save neurons.”
   ALS researchers at CUMC have already started such investigations. Tens of thousands of compounds are being screened for their therapeutic potential by Christopher Henderson, Ph.D., co-director of the Motor Neuron Center and professor of pathology. Dr. Przedborski’s lab is working to identify the unknown toxin, or toxins.
   There are still many questions to answer, however, before it is known whether astrocytes play a deleterious role in all ALS patients, most of whom have normal SOD1 genes.
   “We do not know yet if astrocytes in patients with normal SOD1 release a toxin,” Dr. Przedborski says. “If the answer is yes, then our findings could be a critical piece of the puzzle, but we still have a long way to go.”
The research was supported, in part, by the Muscular Dystrophy Association’s Wings Over Wall Street, the ALS Association, Project ALS, the NIH, U.S. Department of Defense, the Parkinson’s Disease Foundation, and the Bernard and Anne Spitzer Fund.

—Susan Conova

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