The Astrocyte AccomplicesStudies provide clues as to what causes motor neuron deterioration in ALS
Astrocytes become toxic to motor neurons in both familial and sporadic forms of ALS.
In studies of ALS, motor neurons were thought to be the key player. It is, after all, the motor neurons that wither and die, leading to the symptoms of ALS. Figuring out the disease process in motor neurons, researchers thought, would crack the mysteries of ALS, allowing scientists to work for better treatments and maybe even a cure.Packard scientists, however, have been studying for some time how the cells that normally help motor neurons behave (or misbehave) in disease. Normally, astrocytes function as a secretary to their motor neuron executives. Instead of scheduling appointments and managing correspondence, astrocytes make sure that the motor neuron has enough energy and that it has structural support. A recent study by P2ALS scientist Brian Kaspar at Nationwide Children’s Hospital and The Ohio State University showed that common ALS-triggered changes could cause astrocytes to become toxic to motor neurons in both familial and sporadic forms of ALS. This study indicates astrocytes, even from human patients, can cause the death of motor neurons, highlighting their importance as a cellular target in this disease. “Astrocytes are a common cell type. The cells show similar profiles in both familial and sporadic forms of ALS, as well as what happens from a molecular and pathological standpoint. That is, they turn on inflammatory genes. Exactly how these genes get turned on could vary between familial and sporadic cases,” Kaspar said. Astrocyte spotlight.
| Brian Kaspar
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Previous studies looking at the potential link between astrocytes and ALS focused mainly on familial forms of the illness that resulted from mutations in SOD1. Although researchers did show that astrocytes with abnormally high levels of mutant SOD1 proteins caused motor neuron death, familial ALS cases with SOD1 mutations only explain about two percent of all ALS cases. Kaspar and his colleagues wanted to know if toxic astrocytes were linked to the sporadic form of ALS.Kaspar gathered neural progenitor cells (NPCs) post-mortem from the spinal cords of seven sALS patients and one fALS patient. The researchers then coaxed the NPCs into becoming astrocytes. After confirming the NPCs had differentiated into mature astrocytes, Kaspar and colleagues tested how these astrocytes affected healthy motor neurons derived from mouse embryonic stem cells. When the scientists placed the mouse-derived motor neurons in culture along with the astrocytes from ALS patients, the motor neurons began to die. Motor neurons cultured with control astrocytes did not show signs of disease. Further experiments showed that astrocyte toxicity was limited to motor neurons – no other neuron types showed signs of degeneration. Most noteworthy, perhaps, was the fact that the astrocytes from sALS patients did not have any mutations in SOD1, TDP-43, or other genes implicated in ALS. Yet when Kaspar and colleagues decreased the amount of SOD1 present in the astrocytes derived from sALS patients, motor neuron death also decreased, even though the astrocytes were producing the wild-type (normal) version of SOD1. Kaspar believes that the problem might be how the protein is folded. The identities of individual amino acids usually provide a template for the final shape of a protein. But just as an origami master can transform the same sheet of paper into a swan or a flower, the same protein can have more than one shape. Some misfolded proteins, like SOD1, are highly toxic to the cell, which might contribute to the development of sALS. “This study shows that SOD1 can be a potential target for the treatment of ALS, not just for those patients who have an SOD1 mutation, but also those without this mutation,” Kaspar said. “Astrocytes are implicated when you have an SOD1 mutation, and when you don’t have this mutation.” Moving forward.This study will help researchers understand both the similarities and differences between the familial and sporadic forms of ALS, Kaspar says. Although both types of ALS may have the same end result – motor neuron deterioration and death – it may happen through different pathways depending on whether the disease is sporadic or inherited.“The big question is why these astrocytes are getting so aggravated that they kill motor neurons. The field is just starting to test that aspect now,” Kaspar said. –– Carrie Arnold
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