Junctioning to conclusions: Exploring neuromuscular junction vulnerability to uncover new therapeutic targets and biomarkers for ALS

Motor neurons are specialized cells in the brain that are responsible for controlling voluntary muscles. In ALS, these neurons break down and die, eventually leading to weakness, then paralysis of muscles. Besides motor neuron degeneration, an early sign of ALS is the loss of the neuromuscular junction (NMJ), the connection point between muscles and motor neurons. In the disease, the neuron terminals at the junction begins to retract, a process called denervation, leading to a disconnection between the brain and muscles.

Recent studies have shown that the loss of NMJs may occur even before significant degeneration of the motor neurons themselves. For some researchers, this suggests that the NMJ is not only a passive target of the disease but may play a significant role in ALS progression. Dr. Lafont’s research project aims to delve deeper into the molecular and functional differences that dictate how NMJs respond to denervation, particularly in various conditions like aging and ALS. She aims to uncover why some NMJs are more resilient to damage while others appear to be more susceptible to it. Understanding these changes and NMJ vulnerability could provide critical insights into developing new therapeutic approaches and identifying biomarkers for NMJ disruption. Identifying biomarkers associated with NMJ damage may also help in earlier diagnosis and monitoring disease progression, a crucial area for ALS clinical care.

The ALS Canada Research Program has proudly supported novel work in the neuromuscular field since 2002. Dr. Lafont’s supervisor, Dr. Richard Robitaille, a globally respected leader in the field, has been supported multiple times. Our awards provided seed funding to what would culminate in an exciting clinical trial in 2024. Dr. Robitaille discussed the neuromuscular junction and his trial investigating a compound called darifenacin in an episode of our ALS Clinical Trial Unboxed series.

Funding for Dr. Agathe Lafont’s Postdoctoral Fellowship was made possible through a partnership with Fondation Vincent Bourque, who generously contributed $82,500 to ALS Canada, which Brain Canada matched through the Canada Brain Research Fund (CBRF).