Two papers by Columbia and Harvard researchers report for the first time that astrocytes (the most abundant non-neuronal cells in the central nervous system), which carry a mutated gene known to cause some cases of amyotrophic lateral sclerosis (ALS/Lou Gehrig's disease), induce motor neuron death.
This indicates that astrocytes may contribute to ALS by releasing a toxic factor that damages neurons. These findings, posted online by Nature Neuroscience on April 15, suggest that developing an effective therapy for ALS would require overcoming the destructive effects of astrocytes and replacing the damaged motor neurons, possibly by transplanting motor neurons derived from embryonic stem cells.
In ALS, there is a progressive degeneration of motor neurons, leading to paralysis and eventual death. In single cell culture studies at Columbia University Medical Center, Serge Przedborski, M.D., Ph.D., co-director of the Center for Motor Neuron Biology and Disease, and his colleagues found that astrocytes expressing a mutated form of a gene, superoxide dismutase (SOD1), killed only the neurons that degenerate in ALS, not other types of neurons, and that this was due to a soluble toxic factor released by the astrocytes. If this toxic factor can be identified in future studies, this finding may offer novel strategies for ALS therapy.
Astrocyte Cells Not Spectators, But Key Players
“It was previously thought that astrocytes were merely spectators watching their neighboring motor neurons die,” said Dr. Przedborski, who is the Page & William Black Professor of Neurology and professor of pathology and cell biology at Columbia's College of Physicians & Surgeons. “With these results, we have learned they are not just spectators, they are major players. The astrocytes and their cellular environment are specifically causing motor neuron death.
“If these cell culture findings are faithfully modeling the situation occurring in ALS, then blocking the toxic factor released by astrocytes as early as possible could become an effective neuroprotective strategy against this disease,” Dr. Przedborski added. “Currently, we diagnose ALS at a point when a large number of motor neurons are already gone. As we learn more about astrocytes and the toxic factor or factors they release, we may be 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.”
Dr. Przedborski's vision is to eventually test for the “biomarkers” of astrocytes and toxic factors in human ALS patients and then neutralize these factors early in the process thereby stalling or eliminating the degeneration of motor neurons and the onset of debilitating ALS symptoms.
Additional Columbia researchers who contributed to this study include: Tetsuya Nagata, M.D., Ph.D., Diane B. Re, Ph.D. and Makiko Nagai, M.D., Ph.D. of the Center for Motor Neuron Biology and Disease; Alcmène Chalazonitis, Ph.D. from the Department of Pathology and Cell Biology; Thomas Jessell, Ph.D., professor of biochemistry and molecular biophysics, Howard Hughes Medical Institute investigator, and director and research adviser for the Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research; and, Hynek Wichterle, Ph.D., assistant professor of pathology, whose seminal work in 2002 showed that mouse stem cells could be manipulated to become motor neurons.
The Columbia's team astrocyte findings were corroborated in another Nature Neuroscience study authored by Kevin Eggan, Ph.D., Thomas Maniatis, Ph.D. and colleagues at Harvard University and the Harvard Stem Cell Institute. Harvard and Columbia researchers discovered their similar research through ongoing collaboration with the Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research in New York.
This work was supported by the National Institute of Neurological Disorders and Stroke, the U.S. Department of Defense, the Muscular Dystrophy Association/Wings-over-Wall Street, the ALS Association, the Parkinson's Disease Foundation, the Bernard and Anne Spitzer Fund, and Project A.L.S.
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