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Astrocytes Toxic to Motor Neurons

August 15, 2011

A new study published in the August 10, 2011 edition of Nature Biotechnology hindicates further evidence that astrocytes have a toxic affect on motor neurons.  Although there has been growing evidence for this and several studies in culture indicating that astrocytes from ALS mice are toxic to motor neurons, this is the first study using human astrocytes isolated from ALS patients in a living system, i.e., a mouse model.

The investigators noted that lowering levels of SOD1 in the astrocytes obtained from individuals who died from both familial and sporadic ALS, decreased the toxicity to the motor neurons providing further support that SOD1 may be important in mediating the disease not only in those cases with mutations in the gene but also in people with sporadic ALS.

Using autopsy tissue taken from people who died from ALS, researchers funded by the National Institutes of Health (NIH) developed a new model of the disease and found that astrocytes become toxic to motor neuron cells, consistent with earlier studies using mouse models in which mutant SOD1 was restricted to the mouse astrocytes and neighboring neurons were affected.  This new study could further help unlock many mysteries surrounding ALS.

Only a small percentage of ALS cases are familial; the majority of cases are sporadic, which has no known cause.  The researchers used astrocytes gathered from people who succumbed to both types of the disease and found that the cells secreted toxic factors that caused motor neurons to degenerate.  This result has been previously observed in ALS animal models.

"The mouse models capture a type of familial ALS that accounts for only 2 percent of all cases.  The field has begged for new disease models that can provide a clear window into sporadic ALS," said senior author Brian Kaspar, Ph.D., an investigator at the Nationwide Children's Research Institute (NCRI) in Columbus, Ohio.

Further experiments revealed that the SOD1 plays a critical role in the toxicity.  The investigators used a method called RNA interference to silence the SOD1 gene.  RNA serves as an intermediary between genes and proteins, but in RNA interference, small RNA fragments are used to block a gene from making proteins.  When the researchers used a virus to deliver such small RNAs to astrocytes affected by familial ALS, the astrocytes were no longer toxic to motor neurons.  This method also suppressed toxicity in four of six astrocyte lines derived from people with sporadic ALS, supporting the idea that the SOD1 enzyme also has a role in sporadic cases.

“Studies are currently underway in mouse models of ALS to determine whether astrocyte replacement would be a feasible therapeutic approach,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D.  “This published work provides further support for this concept.  Visit http://www.alsa.org/news/archive/stem-cell-research1.html to read about related research activity.”

One of the other authors of this study, Amanda Phillips, Ph.D., Department of Neurology, Johns Hopkins University, Baltimore, MD, was recently named by The ALS Association as a recipient of the Milton Safenowitz Postdoctoral Fellowship.  Dr. Phillips is currently doing related work in the laboratory lead by Nicholas Maragakis, M.D.  Visit http://www.alsa.org/news/archive/2011-new-research-grants-1.html to review the grant announcement.

“We are particularly excited about this work as we now have an opportunity to further study defined cell types, such as astrocytes from familial SOD-1 linked and sporadic ALS patients,” continued Dr. Kaspar.  “The hard work lies ahead as we work to determine the toxicity of these patient derived astrocytes.”

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