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

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.

One of the primary energy sources of the nervous system is glucose, followed by lactate, a small sugar molecule. The researchers unexpectedly discovered that oligodendroglia express a transporter protein called MCT1 that can move lactate in and out of the cell, and that this transporter supplies neurons and their axons with energy enriched lactate. If motor neurons could not get enough energy in the form of glucose or lactate, then they would begin to degenerate, which is exactly what researchers saw in ALS. A malfunctioning MCT1 protein in oligodendroglia could consequently lead to motor neuron deterioration because the cell would not get enough energy.

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 a lack of lactate was leading to motor neuron deterioration. 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. These results hint at a new physiological role for oligodendroglia and a new understanding of ALS disease.

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. 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.