Project Description: All of our daily movements, including breathing, require healthy connections and signaling between motor neurons and muscles. Neuron-muscle communication throughout our bodies is mediated via a common structure called the neuromuscular junction (NMJ). Defects in NMJ integrity and function underlie fatal diseases such as Amyotrophic Lateral Sclerosis and Spinal Muscular Dystrophy. Though NMJ diseases affect over a half million people globally, effective treatments or cures are currently lacking.
It is not well understood how the human NMJ is built and maintained. Thus, understanding the cell biology of the human NMJ in health and in disease is an essential first step toward developing targeted therapeutic approaches. This project aims to develop new tools and knowledge to address these questions. Using iPSCs derived from reprogrammed skin cells of healthy persons, the investigators will develop human neuromuscular junctions in 3D culture. Using quantitative hi-resolution imaging techniques, the investigators will define key characteristics of the cellular architecture and operation of the healthy human NMJ synapse. The investigators will then determine how the process of synapse formation, maturation, and function is perturbed across different ALS patients by examining NMJs built from patient cells. Finally, the investigators will define the involvement of a protein quality control regulator they found to be downregulated in ALS neurons on NMJ health. These findings will allow the investigators to identify candidate genes to target and improve the health of the diseased NMJ synapse in follow-up studies, for example by preventing or delaying NMJ degeneration or by promoting NMJ repair and regeneration.