Many scientists believe that one of the earliest abnormalities in ALS is dysfunction at the place where motor neurons connect to muscle, known as the neuromuscular junction (NMJ). Dr. Charles Krieger has observed that a substance called adducin, which is critical to the structure of the NMJ, is altered in multiple animal models of ALS. As a result, Dr. Krieger has hypothesized that abnormal levels or regulation of adducin may be responsible for this early NMJ dysfunction. In this Discovery Grant, Dr. Krieger will collaborate with NMJ expert, Dr. Richard Robitaille of the Université de Montréal to further examine the role of adducin in ALS. Using two different animal models (fruit flies and mice), representing two different genetic causes of ALS (TDP-43 and SOD1), they will examine the mechanisms of adducin alteration by looking at its regulation and the various proteins it interacts with to properly maintain NMJ structure. Boosting NMJ health may represent an important avenue to slow down ALS and unraveling the role of adducin in maintaining this may provide unexplored new targets for treatment.