Friendly Neighbors May Become Neuron Killers
24 Apr, 2007 01:11 pm
Neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS), are characterized by a loss of specific subsets of brain cells called neurons. Because it is the neurons that are specifically dying, it has been traditionally thought that the disease process of ALS has to occur within neurons from beginning to end. However, recent findings as those from researchers at Columbia University make it clear that other brain cells may play a key role in loss of neurons in ALS. In this adult-onset neuromuscular disease, there is a progressive degeneration of spinal cord motor neurons (the neurons innervating muscles) leading to a gradual paralysis and eventually death, mainly by respiratory failure. ALS is usually fatal within 5 years after diagnosis and no cure or treatment prolonging life by more than a few months has been found.
The new report from Columbia University researchers, posted online by Nature Neuroscience on April 15, 2007, shows in a cell culture model of ALS, that astrocytes, the most abundant non-neuronal cells in the central nervous system, are not only witness to the suicide of their motor neuron neighbors but may be an accomplice in their demise. Serge Przedborski, M.D., Ph.D., Professor of Neurology and co-director of the Center for Motor Neuron Biology and Disease, and his colleagues studied the effect of astrocytes on the fate of spinal motor neurons. They found that these mutant astrocytes kill only motor neurons via a toxic factor released by the mutant astrocytes.
The identification of this astrocyte toxin represents a major challenge, as the development of strategies to block this toxic factor, as early as possible in the disease process, could become an effective protective therapy for ALS. Future studies will tell whether this factor can be used as a diagnostic tool. Currently, ALS is diagnosed at a point when a large number of motor neurons have already died. A better characterization of this toxic factor may render possible screening people for elevated levels of this molecule and intervene in a tangible way perhaps even before a person displays any clinical sign of ALS.
Motor neurons produced from embryonic stem cells have emerged as a potential repair reagent for the treatment of spinal cord diseases such as ALS. Przedborskiís laboratory study and 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, show that ALS mutant astrocytes also kill motor neurons originating from stem cells. This fact suggests that optimal result with stem cells may have to be combined with additional therapeutics to abate the hostile cellular environment in which they will be engrafted and which may challenge their ability to survive and grow processes.
The co-culture system set-up by this Columbiaís team, combining ALS mutant astrocytes and motor neurons produced from stem cells, which are readily expandable, offer an invaluable cellular tool for screening of small neuroprotective molecules that may be relevant for ALS therapy.
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 embryonic stem cells could be manipulated to become motor neurons. 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 Parkinsonís Disease Foundation, the Bernard and Anne Spitzer Fund, and Project A.L.S.
M. Nagai et al., Nature Neuroscience, 15 April 2007