Motoneurons and muscles connect via structures called neuromuscular junctions. Image credit: Doctor Jana (CC BY 4.0)
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal neurodegenerative disorder. It occurs when the neurons that control muscles – the motoneurons – disconnect from their target muscles and die. This causes the muscles to weaken and waste away. More and more muscles become affected over time until eventually the muscles that control breathing also become paralyzed. Most patients die within two to five years of diagnosis.
Motoneurons consist of a cell body plus a cable-like structure called the axon. The cell body of each motoneuron sits within the spinal cord, and the axon extends out of the spinal cord to the motoneuron’s target muscle. Within the muscle the axon divides into branches, each of which connects with multiple muscle fibers. The breakdown of these connections, known as neuromuscular junctions, is one of the first signs of ALS.
Does a motoneuron lose all of its connections with muscle fibers at once, or do the connections break down a few at a time? This distinction is important as it will help to identify the events that lead to muscle paralysis in ALS. To find out, Martineau et al. studied mice that had two genetic mutations: one that causes ALS and another that produces fluorescent molecules in some motoneurons. This allowed the branches of the motoneurons to be tracked over time with a fluorescence microscope.
Martineau et al. found that individual neurons lose their connections to muscle fibers gradually. Moreover, motoneurons grow new branches and form new connections even while losing their old ones. This dual process of pruning and budding lasts for several weeks, until eventually the motoneuron dies.
Developing drugs to stabilize neuromuscular junctions during the period when motoneurons gradually disconnect from muscles could be a promising avenue to explore to improve the quality of life of ALS patients. One advantage of this treatment strategy is that neuromuscular junctions in muscles are easier to access than motoneurons inside the spinal cord. To identify potential drugs, future studies will need to focus on the proteins and signals that cause the neuromuscular junctions to break down.
