Embryonic Stem Cells Show ALS Can Arise From Support Cells

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Researchers funded by The ALS Association at Harvard laboratories led by Tom Maniatis, Ph.D., and Kevin Eggan, Ph.D., published online in Nature Neuroscience that stem cell-derived motor neurons are killed by the glial cells that are supposed to serve them.

Our studies demonstrate that glial cells carrying a SOD1 human mutation have a direct effect on motor neuron survival and provide a powerful tool for studying the mechanisms of neural degeneration

Experiments with mouse embryonic stem cells show that the supporting cells of the nervous system, if mutated, can kill motor neurons in a cell culture, providing a new and powerful tool to develop therapy for ALS.

Researchers funded by The ALS Association at Harvard laboratories led by Tom Maniatis, Ph.D., and Kevin Eggan, Ph.D., published online in Nature Neuroscience that stem cell-derived motor neurons are killed by the glial cells that are supposed to serve them.

The glial cells that normally surround and nourish motor neurons proved lethal if they had the mutation linked to some inherited forms of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease for the baseball player who died of it in 1941). This was true for motor neurons growing with the mutant glia in lab dishes, whether or not those motor neurons had the ALS-linked mutation.

Monica Carrasco, Ph.D., who is one of the recipients of The Milton Safenowitz Post-Doctoral Fellowship for ALS Research, is working with mentor Maniatis and collaborating experts in stem cell and motor neuron biology at Harvard and elsewhere on research directions that led to these findings (Click here for more information.)

All cells in the test system came from mouse embryonic stem cells, enabling a simple means to dissect a complex disease process. With this stem cell-based approach, the researchers are pioneering a powerful new tool that should lead to a therapeutic success story for a fatal disease.

The scientists took stem cells from mice with a normal human gene and also mice with mutant copper-zinc superoxide dismutase (SOD1), a protein defect that somehow produces the disease in about five percent of human cases. As the SOD1-mediated disease is clinically indistinguishable from other forms of ALS, researchers for the past decade have focused on mice engineered to make mutant SOD1 protein. While much has been learned about the disease process, the lessons so far only reinforce how complex a process it is and have yet to yield a targeted therapeutic approach.

Now, with stem cells, the Harvard teams have an incredibly simple system with which to address the complexities of ALS.

"Our studies demonstrate that glial cells carrying a SOD1 human mutation have a direct effect on motor neuron survival and provide a powerful tool for studying the mechanisms of neural degeneration," the scientists wrote in their report, noting the stem cell derived system "could provide cell-based assays for the identification of new ALS drugs."

The motor neurons from stem cells of mice with the mutant SOD1 protein show, in culture, the hallmarks of the disease at the cellular level. They have abnormal protein deposits, consisting of the mutant SOD1 protein, and increased amounts of the molecular tag that cells use to signal that damaged protein needs to be removed. Also, the motor neurons from mutant mouse stem cells show activation of the cell death pathway, another parallel to what takes place in the disease.

A report in the same issue of the journal by Serge Przedborski, M.D., Ph.D., and colleagues at Columbia University, funded by The ALS Association, shows that the SOD1 mutant glia are secreting a substance that is toxic only to the motor neurons and not to other cells. Future investigation with the new strategies developed by these research groups will undoubtedly produce important progress in the search for therapeutics to treat ALS effectively. These collaborative efforts will be key for future progress.

For more information, refer to The ALS Association's Web site under the research tab for further information about stem cells in ALS.

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