Glial Cells Central Factor in ALS

By Richard Robinson

Motor neurons die in ALS, but it is the glial cells surrounding them that may be largely at fault, according to Don Cleveland, Ph.D.  The good news is that glia can be targeted with drugs, genes, or stem cells, pointing the way to developing therapies to correct their damaging behavior.  Dr. Cleveland, from the University of California at San Diego, summarized a decade of work that has established the role of glia in ALS and outlined the way forward in therapy development.

While much of the work showing glial involvement in ALS has been done in the SOD1 genetic mouse model, the results are likely to be relevant to sporadic forms of ALS as well.

There are at least nine different proposals for how mutant SOD1, the most common known genetic cause of familial ALS, leads to motor neuron death.  “They are likely all correct,” Dr. Cleveland said, “which is good news.  If all of them are part of the problem, correcting any one of them may help reduce damage to motor neurons.”

Many of the proposed mechanisms of damage act through glial cells.  Glial cells include astrocytes, which provide metabolic support for motor neurons, and microglia, immune system cells in the central nervous system.

A key finding implicating glia was that mice, which express mutant SOD1 only in their motor neurons and not in their glia, fare much better than those expressing it only in their glia and not in their motor neurons. These results were confirmed and extended recently by the laboratory of Nicholas Maragakis, M.D., of Johns Hopkins University in Baltimore, M.D. Dr. Maragakis presented his research indicating that mutant SOD1 in astrocytes alone was enough to cause motor neurons to die.  Taken together, these experiments confirm the central role of astrocytes in ALS. This is a surprising result, since for a long time, researchers believed that it was the motor neuron’s expression of the mutant gene that was the problem. But the new understanding of the disease process indicates that glia expressing the mutant gene are likely responsible for much of the damage to motor neurons.

One likely reason is that when mutant SOD1 is expressed in astrocytes, it reduces the amount of a crucial protein called the glutamate transporter.  This protein prevents damage to the motor neuron by a chemical called glutamate.  Glutamate is needed by the neuron to send nerve signals, but a build-up of it is toxic.

There are several strategies for reducing the effects of mutant SOD1 expression in glial cells.  In each case, the challenges are how to get the therapy into the central nervous system; how to get it into the astrocytes; and, once inside, how to either reduce SOD1 expression or compensate for its ill effects.

A protein called Activated Protein C has shown some potential in animal models of ALS and has the added benefit of already having approval from the United States Food and Drug Administration for use in humans to treat severe bacterial infection in the blood.  At the moment, though, it is prohibitively expensive to produce, and therefore; impractical for therapy.

One approach moving into clinical trials now is the use of “antisense DNA,” a small piece of genetic material that clings to the genetic code for mutant SOD1, which inactivates it.  A small clinical trial of this therapy is underway, delivering the treatment directly into the spinal cord.

Another approach, currently in final testing in animal models, is to introduce healthy glial cells (derived from stem cells) directly into the spinal cord to tip the balance back toward normal glial function to support motor neurons.  “We are committed to beginning a Phase I trial in ALS patients by 2014,” Dr. Cleveland said.  For more information about this study, visit http://www.alsa.org/news/article.cfm?id=1654

Meanwhile, Jeff Rothstein, M.D., Ph.D., Professor of Neurology at Johns Hopkins University, has unexpectedly found that another type of glial cell, called the oligodendrocyte, may also play a role in ALS. “Oligos” provide the electric insulation that wraps around neurons and serve other functions in the brain as well.  Dr. Rothstein’s work has revealed that a transporter protein called MCT-1 is expressed in oligos far more than in astrocytes.  MCT-1 is important, he said, because it is used to provide neurons with lactate, an energy source.  MCT-1 expression is reduced in ALS patients, which may contribute to the death of motor neurons.  Addressing deficiencies in oligodendrocytes may be yet another way to support motor neurons in ALS patients, Dr. Rothstein said.