Muscles are made of separate fibres bundled together that receive signals from motor neurons, causing the muscles to contract or relax. Motor neurons connect to individual muscle fibres connect to at tiny places called neuromuscular junctions where specialized glial cells called perisynaptic Schwann cells (PSCs) keep the connections functioning well in a healthy body.

PSCs usually perform a maintenance role, keeping the neuromuscular junctions functioning well, but when disease or injury is present, they switch to a repair role, removing the injured nerve terminals that contact muscle fibres and cleaning them so that the connections can be rebuilt. Once the connections are fixed, the PSCs switch back performing their usual maintenance duties.

In ALS, destruction of the connections in the neuromuscular junctions takes place early in the disease progression, leading to eventual muscle weakness and paralysis. Dr. Richard Robitaille, a researcher and professor at the Université de Montréal, has been studying neuromuscular junctions for over 30 years. He discovered that in the presence of ALS, PSCs do not switch effectively from maintenance mode to repair mode. Over time, the lack of repair of the neuromuscular junctions causes the motor neurons to lose their ability to communicate with muscle fibres that are essential for the ability to walk, talk, eat, swallow and breathe. Understanding how and why PSCs do not work properly in ALS would help prevent the degeneration of the neuromuscular junctions.

But one of the great questions about ALS that has not been well-studied is why the motor neurons that control eye movements are more resistant to the ravages of the disease. As ALS progresses, motor neurons controlling muscles called extraocular muscles eventually do become damaged, but they are usually one of the last motor neurons in the body to be affected. It’s fairly common for people with paralysis in the majority of their body from well-advanced ALS to be still able to communicate through assistive-technology devices using eye movements.

“There must be an underlying reason why neurons and their neuromuscular junctions controlling extraocular muscles are more resistant to ALS disease progression than other motor neurons in the body,” said Dr. Robitaille. “Nobody yet has investigated why the neuromuscular junctions are better preserved in these muscles in comparison to other muscles and what are the differences in the PSCs functions and properties.”

Dr. Robitaille recently received a $122,000 grant from the ALS Canada Research Program to investigate the differences between neuromuscular junctions in eye muscles and leg muscles of mice. Using mice that have been altered to express the SOD1 gene mutation associated with human ALS, he will examine PSCs at the neuromuscular junctions in two different leg muscles and the extraocular muscles at two stages of the disease — before and after symptoms appear. “I predict that the PSCs in muscles controlling eye movements will be comparable to those found in healthy mice, allowing for proper communication, maintenance and repair functions,” said Dr. Robitaille. Second, he will investigate which proteins are present and in what quantities to see if he can identify differences that scientists could one day take advantage of to develop targeted therapies.

“If I can identify protective processes in extraocular connections during ALS and discover differences in the presence of proteins found in neuromuscular junctions, I hope that in the future, we may be able to apply that learning to slow degeneration in vulnerable neuromuscular junctions,” said Dr. Robitaille. “Ultimately, this new avenue of research may help identify future treatments that could slow disease progression and improve the quality of life of people living with ALS.”

This research project is one of 12 funded by the ALS Canada Research Program in 2017 following a rigorous scientific assessment by panels of global ALS experts. The panelists evaluated a larger pool of applications to identify the projects that are grounded in scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.

ALS Canada is a registered charity that receives no government funding. Everything we do – from funding research to providing community-based support for people living with ALS – is possible only because of donor generosity and partnerships with provincial ALS Societies who contribute to the ALS Canada Research Program.

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