We are using Drosophila models to study Amyotrophic Lateral Sclerosis (ALS). ALS, also known as Lou Gehrig’s Disease, is a devastating, and invariably fatal, neurodegenerative disorder that strikes during adulthood and causes rapid, progressive loss of motor neurons. Existing fruit fly models overexpressing disease-causing alleles of genes such as Tdp43, Fus, and c9orf72(G4C2)n recapitulate many aspects of ALS in humans, including neuronal degeneration, reduced lifespan, and locomotor defects. However, expression of disease genes and the appearance of their related phenotypes in these models begins during development or immediately thereafter, in contrast to the human disease where the average age of diagnosis is 55. Therefore, in order to generate fly models that more closely mimic human ALS, we are testing strategies that block the expression of disease genes during development, thus creating a true adult-onset model of the disease. We are examining the functional effects of ALS gene expression in adult flies by assessing effects on lifespan, locomotor activity, and motor neuron morphology. We are also testing the effects of gain- and loss-of-function for candidate ALS modifier genes (which were identified in a previous genetic screen conducted in the Artavanis-Tsakonas lab) in these adult-onset models.