Cells that Normally Protect Motor Neurons Acquire Toxic Effects in ALS, Study Suggests

Several studies have shown that oligodendrocytes, cells that normally protect neurons, can also contribute to neuronal death in amyotrophic lateral sclerosis (ALS). Now, researchers demonstrate this toxic turn of events and show how these cells induce neuronal death. This finding may encourage new therapies for ALS to target the dysfunctional activity of these cells.

The study, “Oligodendrocytes Contributed To Motor Neuron Death In ALS Via SOD1 Dependent Mechanism,” was published in the journal Proceedings of the National Academy of Sciences.

Previous studies have reported that brain cells whose function is to feed and protect neurons, such as astrocytes and microglia, can become dysfunctional in ALS, and instead contribute to the pathology of the disease.

In addition, researchers have shown that in mice, another type of brain cells, the oligodendrocytes, which have a crucial role in protecting motor neurons (neurons that stimulate muscles), are also involved in ALS progression. But in humans, this association has not been addressed before.

“We were able to dig deep in trying to make a bridge between a mouse model and what is happening in humans,” Brian Kaspar, PhD, and the study’s leading author, said in a news release. “We have been able to begin asking questions about how exactly oligodendrocytes go wrong and how they lead to motor neuron death.”

But how? Researchers took skin samples from patients with a family history of ALS (familial ALS) and sporadic ALS (the most common form), as well as from healthy subjects, and used modern laboratory techniques to turn skin cells into neural progenitor cells, a type of parent cells that will later “give birth” to several types of brain cells, including oligodendrocytes.

The team observed that the ALS patient-derived oligodendrocytes induced death of motor neurons in culture in a process dependent on an enzyme called SOD1, which was mutated in both familial and sporadic ALS patients. For that reason, the team depleted the “parent” cells of SOD1, so that the derived oligodendrocytes would no longer be able to trigger neuronal death mediated by this protein. Indeed, these SOD1-lacking oligodendrocytes did not induce motor neuron death.

However, when researchers tried to inhibit SOD1 in the newly formed oligodendrocytes without any changes in the “parent” cells, they could not avoid motor neuron death. This result showed that when ALS oligodendrocytes are fully matured and have functional SOD1, they will induce neuronal death.

“There is a point of no return,” Kaspar said. “When these cells have reached a certain point of differentiation or in their toxicity profile, you can’t reverse it. This tells us to treat as early as possible, which is an emerging theme in many neurodegenerative disorders.”

Additional studies are necessary to further study cell dysfunction associated with ALS, using, for instance, these methods that allow researchers to obtain specific cell types from skin samples of patients.