Pioneering research led by The University of Sheffield in the United Kingdom reveals that a type of cell in the central nervous system that usually supports motor neuron function can "go rogue" and destroy motor neurons in people with ALS.

[wide myelin tree that develops from the central cell body]Share on Pinterest
Here, in green, captures the wide myelin tree that develops from the central cell body. In ALS, these cells gain toxic properties and cause cell death.
Image credit: The Sheffield Institute for Translational Neuroscience (SITraN)

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Motor neurons - nerve cells that form a pathway for the brain to send instructions to muscles - degenerate in ALS and lead to weakness and wasting of muscles.

There are two types of ALS: sporadic and familial. The sporadic form of the disease accounts for 90-95 percent of all cases in the United States and occurs at random with no clearly associated risk factors, while familial ALS - which accounts for 5-10 percent of all U.S cases - is inherited.

An international team of researchers - directed by Dr. Laura Ferraiuolo from the Sheffield Institute of Translational Neuroscience (SITraN) at The University of Sheffield - made the groundbreaking discovery of how the oligodendrocyte brain cell plays a significant role in the progression of ALS.

Dr. Ferraiuolo began the research at The Kaspar Laboratory based at the Centre for Gene Therapy at the Research Institute at Nationwide Children's Hospital (RINCH) in Columbus, OH, as part of her EU-funded Marie Curie Fellowship.

Oligodendrocytes are a type of glial cell that surrounds neurons and provides support and insulation between them. Their primary function is to produce myelin that wraps around the neurons and allows signals to run faster, which helps communication from one neuron to another.

The team uncovered that oligodendrocytes - which typically assist with neuron function - can become destructive and cause cell death after developing an innovative oligodendrocyte in-vitro model from the skin cells of people with ALS. "This is the first human in vitro model allowing us to study the specific interaction between neurons and oligodendrocytes from ALS patients," says Dr. Ferraiuolo.

Dr. Ferraiuolo and colleagues also found that decreasing the levels of the gene SOD-1 can rescue the adverse effect of rogue oligodendrocytes on motor neurons. At least 200 mutations in the SOD-1 gene have been associated with causing ALS.

Previous studies have identified other glial cells - astrocytes and microglia - that contribute to motor neuron death in ALS. The researchers detected the behavior of oligodendrocytes through mouse and human studies using the "direct conversion" method.

Direct conversion is a method developed by Prof. Brian Kaspar and his team at the Kaspar Laboratory to generate neural progenitor cells (NPCs) from skin cells.

Supporting cells from familial, sporadic ALS result in cell death

Neural progenitors are cells that, like stem cells, can differentiate into a particular type of cell, although they are already more specific than stem cells. NPCs are capable of dividing a limited number of times and have the capacity to differentiate into neuronal and glial cell types such as astrocytes and oligodendrocytes.

In this instance, the direct conversion method was used to model ALS by differentiating the produced NPCs into oligodendrocytes derived from skin cells collected from people with familial ALS and sporadic ALS.

The study findings - published in the journal Proceedings of National Academy of Sciences - show that the oligodendrocytes from both familial and sporadic ALS patients result in motor neuron death.

However, in contrast, oligodendrocytes from healthy people or those with other neuromuscular disorders left motor neurons unharmed. The researchers suggest that this finding indicates the distinct phenotype to ALS-derived oligodendrocytes.

"The ability to model the communication between the cells dying during the disease, the motor neurons, and their surrounding neighboring cells is crucial for the development and timing of the therapies. With this rapid reprogramming protocol, we are a step closer to personalized medicine."

Dr. Laura Ferraiuolo

Prof. Kaspar, the senior author of the paper and principal investigator in Columbus, concludes by saying that by using the novel direct conversion method, researchers have been able to interrogate the function of different glial cells in ALS. Consequently, they have begun to understand that "different supporting cells 'go-rogue' at different stages of the disease and contribute to the pathology through different mechanisms."

Read about how ALS could be prevented with technique that halts protein clumping.