ALS Alert Newsletter | July

Neuron support cells play a key
role in ALS

New study in Nature describes new role for oligodendroglia in the brain and their role in the development of ALS

Without the energy provided from oligodendroglia, motor neurons (above) can deteriorate and die.

Packard scientists have identified what may trigger the death of motor neurons in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Motor neurons, which control muscle movement, slowly stop functioning in ALS, which typically causes death within two to five years of diagnosis. Despite decades of study, however, scientists were unsure exactly why motor neurons began to wither and die. A new study published today in Nature by Packard Medical Director Jeff Rothstein has identified a malfunction in neural support cells called oligodendroglia that can cause neuron-including motor neuron degeneration.

"This is a new function for this principal brain cell and we were surprised to find that this cell and its energy support pathway were significantly injured in ALS models and in patients," says Rothstein.

The main function of oligodendroglia is to surround neurons with a layer of insulating lipids known as myelin. This helps the neuron's electrical impulses fire more efficiently, and is crucial to proper neuron functioning. Without myelin, the neuron's long, projecting axon dies. Axon death is a common feature of many neurodegenerative diseases, including ALS. But no one knew exactly what caused this axon death, although more recent studies hinted that oligodendroglia might play a role.

Spotlight on the supporting actors

The researchers unexpectedly discovered that oligodendroglia express a transporter protein called MCT1 that can move a small molecule known as lactate in and out of the cell. Lactate is the nervous system's preferred energy source after glucose, and the MCT1 transporter supplies neurons and their axons with energy enriched lactate. If the MCT1 transporter malfunctioned, Rothstein and colleagues hypothesized, motor neurons could not get enough energy in the form of lactate. Without enough energy, the motor neurons would begin to degenerate, which is exactly what researchers see in ALS. A malfunctioning MCT1 protein in oligodendroglia, then, could ultimately result in motor neuron deterioration.

Jeff Rothstein

Rothstein and colleagues knocked out the MCT1 gene in mice, and found that the axons and neurons began to die. Since MCT1 did not affect the neuron's supply of glucose, the researchers concluded that it was a lack of lactate that led to the motor neuron deterioration, rather than an overall energy deficit. In a cell culture of motor neurons and oligodendroglia lacking MCT1, motor neurons again began to die but were rescued when given lactate. Since only oligodendroglia express MCT1, the researchers knew that the role of this cell type was crucial in providing energy and metabolic support to motor neurons.

In a mouse model of ALS, the researchers found that the oligodendroglia in the brains of the mice stopped expressing MCT1 even before physical symptoms of disease were present. They found a similar absence of MCT1 in oligodendroglia in human ALS patients. A malfunction in oligodendroglia in general and MCT1 in particular, Rothstein concluded, appear to play a possible role in the motor neuron degeneration seen in ALS.

These results hint at a new physiological role for oligodendroglia and a new understanding of ALS disease. Previous research has, not surprisingly, focused on motor neurons as the key players in ALS. This latest study hints that supporting actors like oligodendroglia may have a far more important role in the development of motor neuron disease than previously thought.

Preserving MCT1 function or supplying motor neurons with lactate may one day be a potential therapeutic goal in treating ALS, Rothstein says. Future work will be necessary to understand how oligodendroglia are injured in ALS and how one might repair or prevent this injury.

This work was supported by the Robert Packard Center for ALS Research, P2ALS, and the National Institutes of Health.

–– Carrie Arnold