News from the 2012 ALS/MND International Symposium

Researchers at the Amyotrophic Lateral Sclerosis (ALS) Motor Neuron Disease (MND) International Symposium met for three long and intense days in December 2012 to discuss the newest research on all aspects of ALS.  Below is the summary of one of these important topics. 

The Roles of Nonneuronal Cells in ALS

     Astrocytes and immune cells are shaping up as key players in the ALS disease process

Within the past several years, it has become increasingly clear that non-neuronal cells within the central nervous system play a key role in ALS.  These cells, including cells called astrocytes, usually provide metabolic support for neurons, helping them by removing toxic substances and providing growth factors.  But for reasons still unknown, they can begin to harm motor neurons, leading to dysfunction and eventually death.

Understanding the harm caused by nonneuronal cells is a major research target for ALS scientists.  One of the leaders of that effort is Serge Przedborski, M.D., Ph.D., of Columbia University in New York.  His lab discovered that one such group of cells, called astrocytes, when isolated from SOD1 mutant mice and grown together with motor neurons, lead to motor neuron death.  The team speculates that these astrocytes release an unknown molecule or molecules that are absorbed by motor neurons, increasing their risk of death.  Dr. Przedborski gave an update on the search for the identity of that molecule in his talk, but indicated that to date the identity of the molecule or molecules has not been determined.

His work has led to the conclusion that the mystery molecule is a protein (rather than an ion, or fat, for instance), and he has partially purified it in order to better characterize it.  He has also begun the search for the receptor on the motor neuron that interacts with the protein, both to shortcut the search for the protein’s identity and to better understand the mechanism of toxicity.  The picture is still not entirely clear, but he has identified candidates for the receptor and is steadily homing in on the protein itself.

Kathrin Meyer, Ph.D., working with Brian Kaspar, Ph.D., of Nationwide Children’s Hospital in Columbus, Ohio, outlined her work exploring the toxicity of astrocytes isolated from both familial and sporadic ALS patients.  Motor neurons grown with these astrocytes were at greater risk of death, but that risk could be lessened by reducing the production of the SOD1 protein.  That was true whether or not the SOD1 protein was the normal or mutant form.  That suggests that reducing the level of SOD1 protein may be a useful treatment strategy even in those people whose disease initiation is not due to mutations in the SOD1 gene.

The immune system has long been implicated in playing some role in ALS, although exactly how remains unknown.  Deciphering that role is the focus of the ALS Therapy Development Institute (ALSTDI) in Cambridge, Massachusetts, led by Stephen Perrin, Ph.D.  Dr. Perrin described ongoing work at ALSTDI to identify “druggable targets” that can have an effect on ALS progression.  They are using large-scale gene sequencing approaches, among others, to find such targets, especially in the inflammatory pathways of the immune system.  Inflammation is a coordinated response used to protect against injury and infection, but can be damaging if uncontrolled.  He noted the likely importance of early treatment, since “it becomes very hard to turn off the inflammatory pathway after a certain point.”

Immune suppression, preventing the system from responding, has not been successful in ALS models, but there is some evidence that immune modulation, altering the behavior of certain elements of the system, may be a promising approach.  ALSTDI is currently testing drugs from multiple sclerosis (an autoimmune disease) in models of ALS to test their potential.

More News from the Symposium, visit:

New Understanding of Protein Recycling in ALS:  New genes and new pathways reveal potential new targets for treatment

Why are some Motor Neurons More Vulnerable than Others?  Understanding why ocular motor neurons are spared may lead to protective strategies for all motor neurons

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