As usual, it turns out that your mother was right — the group you surround yourself with might just get you into trouble. Last month in the journal Nature Neuroscience, two groups of researchers reported that in the devastating disease amyotrophic lateral sclerosis (ALS) the cells that die, the motor neurons in the brain and spinal cord, might not be to blame for the disease. Instead, this new research suggests the blame lies with the neurons’ neighbors, cells called astrocytes, which might induce the motor neurons to die.
What is ALS?
ALS, which is also known as Lou Gehrig’s disease, is a progressive, fatal disease involving the death of neurons that control muscles, and therefore movement. These neurons, called motor neurons, are located in the brain and spinal cord and make connections with muscles. The death of these neurons in patients with ALS causes difficulty moving, speaking, swallowing, and breathing. Currently, there is no cure for ALS, and the only approved treatment (Rilutek® or riluzole) can only slightly delay the progression of the disease. Approximately 30,000 people in the United States have ALS. Most people diagnosed with ALS are between 40 and 70 years old, although rare forms can strike children and young adults. Once diagnosed, most people with ALS live for approximately three to five years, although life expectancy is variable.
In order to find better treatments for this devastating disease, scientists have been actively researching the causes of ALS. About 10% of ALS cases are genetic, or heritable, meaning there is a family history of the disease. For the other 90% of cases, ALS seems to strike randomly. However, it is easier to study the heritable cases because scientists have been able to find specific changes in DNA, known as mutations, which underlie the disease in these families. By studying the disease in families with known mutations, scientists hope to find treatments that can be applied to a large number of patients with ALS, even those without a family history. Scientists have extensively researched mutations in a stretch of DNA that is used to make the protein superoxide dismutase 1 (SOD1). Mutations in SOD1 are the most common cause of heritable forms of ALS, but it is unclear how mutant SOD1 triggers the death of motor neurons. The role of normal SOD1 is to act as an antioxidant, detoxifying harmful free radicals that can cause damage to cells. Scientists originally thought that mutant SOD1 might cause ALS by failing to clear up free radicals efficiently, which is called a loss-of-function mutation. Instead, it appears as though mutant SOD1 causes a mysterious new toxic process to occur that is not directly related to SOD1’s role as an antioxidant. This type of mutation is called a gain-of-function mutation.
SOD1 and astrocytes
Because motor neurons are the cells that die in ALS, a lot of ALS research has focused on the motor neurons themselves. But recently, two studies by Francesco Paolo Di Giorgio and colleagues at Harvard, and Makiko Nagai and colleagues at Columbia, have shown that the cells surrounding the motor neurons may play an important role in determining motor neuron health. These surrounding cells, called astrocytes, are a type of glial cell, which are non-neuronal cells in the brain and spinal cord. For a long time, it was thought that glial cells had a mostly passive role in supporting and nourishing neurons. But these studies reveal that the presence of mutant SOD1 in astrocytes contributes to the death of neighboring motor neurons. Healthy motor neurons (with no mutation in SOD1) died when grown next to astrocytes that had a mutation in SOD1. However, motor neurons that had a mutation in SOD1 could survive if they were grown next to healthy astrocytes. The scientists also found that astrocytes with a SOD1 mutation kill motor neurons by releasing an unknown toxic substance onto the motor neurons. These studies suggest that the primary cause of SOD1-induced motor neuron death is the toxic role of SOD1 in astrocytes, not in motor neurons.
These results have important implications for how ALS is treated. If scientists can identify the toxic substance released by astrocytes, they can begin to look for treatments to stop the action of this toxin, thereby leading to a novel treatment for ALS. Also, these studies show that having healthy astrocytes might be of primary importance in preventing or treating ALS. One of the goals of stem cell therapy is to treat diseases such as ALS by replacing the cells that die (i.e. motor neurons) with healthy stem cells that have been cajoled into replacing the dying cell type. However, these studies suggest that for ALS it might be a better idea to convert healthy stem cells into astrocytes, in order to surround motor neurons containing mutant SOD1 with a healthy environment. This is great news for researchers and patients alike, because it will probably be easier to replace astrocytes than it will be to replace motor neurons. Compared to motor neurons, astrocytes are relatively simple cells that make direct connections only with nearby cells. Motor neurons, on the other hand, make connections over long distances, reaching way out to muscles all over the body. Using stem cells to replace motor neurons would be very difficult, because these long-range connections would have to be maintained or recapitulated. Using stem cells to replace astrocytes avoids this complication.
Beyond ALS
These studies provide another important advance in disease research, one that extends far beyond ALS. In order to study ALS in the lab, both groups of researchers used embryonic stem cells from mice to make the motor neurons and astrocytes used in their studies. Some of these stem cells had a mutation in SOD1, and so the motor neurons and astrocytes made from these stem cells mimicked how motor neurons and astrocytes from a patient with an SOD1 mutation would behave. Because stem cells have an unlimited capacity to make more of themselves, having stem cells that carry disease mutations, like SOD1, will allow scientists to study how the disease occurs and test potential treatments on a very large number of cells. Although the experiments in these studies were done using mouse cells, scientists are very excited about the potential of using human stem cells with mutations that cause many different diseases, including ALS, Alzheimer’s disease, cancer, and diabetes. Currently, scientists are prohibited from using federal money to generate these new stem cell lines, but funding from private foundations could be used for such work. If scientists can make human stem cell lines that carry disease-causing mutations, these cells could be used to rapidly screen many different potential treatments.
Stephanie Courchesne, Harvard Medical School
For More Information:
Coverage of the Harvard scientists’ contribution to this research including quotes from the lead researchers:
< http://www.news.harvard.edu/gazette/2007/04.19/99-als.html >
The ALS Association website:
< http://www.alsa.org >
Primary Literature:
Di Giorgio, F.P., Carrasco, M.A., Siao, M.C., Maniatis, T. and Eggan, K. (2007). Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nature Neuroscience, 10, 608-614.
Nagai, M., Re, D.B., Nagata, T., Chalazonitis, A., Jessell, T.M., Wichterle, H., and Przedborski, S. (2007). Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nature Neuroscience, 10, 615-622.