Deciphering the mechanisms underlying synaptic dysfunction at the neuromuscular junction in Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder caused by progressive dysfunction, and later death, of motoneurons innervating skeletal muscle fibers. MNs are the part of the nervous system that control muscles involved in movements such as walking and breathing. They do so because they physically contact muscles where they signal them to contract by releasing a chemical at a site on the muscle known as the neuromuscular junction (NMJ). As the disease progresses, connections between the nervous system and muscles become fewer causing the muscle to become progressively weaker to a point where they are paralyzed. Patients usually succumb to ALS within 2-3 years of diagnosis as a result of an inability to control respiratory functions such as coughing and breathing. There is no cure for ALS and treatment options are limited. ALS occurs sporadically, with no known cause, in 90% of the cases. The other 10% are caused by genetic mutations. Despite this diversity, one of the shared features of the disease is the progressive withdrawal of the motoneurons from the NMJ prior to cell death. This withdrawal speeds up the rate of paralysis and contributes to MN death. This proposal will examine why motoneurons withdraw from the NMJ in ALS. We will combine mouse genetics with electrophysiological, anatomical, biochemical and behavioral techniques to examine whether a group of proteins known BMPs are involved in stabilizing the NMJ in mice (similar proteins are well known to stabilize the NMJ in fruit flies). Furthermore, we will examine how BMPs are misregulated in ALS mice in order to determine how this misregulation affects disease progression. Ultimately, we believe that results will provide a foundation of knowledge to later develop pharmacological interventions that will stabilize the connections between motoneurons and muscle in ALS and thus improve muscle strength and quality of life for those living with the disease.