Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, is a catastrophic neurodegenerative disorder that selectively involves motor neurons in the brain and spinal cord, resulting in progressive muscle weakness and atrophy. It is estimated to affect 2/10000 people, is invariably lethal within 3-5 years, and completely lacks therapeutic treatments. The underlying biology and molecular mechanisms leading to the disease are not well understood. More than 90% of the cases are of unknown genetic origin (sporadic ALS). Genome-wide association studies have identified more than twenty different genes associated with familial ALS (10% of total cases), indicating a complex underlying genetic architecture. Given the paucity of therapeutic interventions there is a great unmet need to develop novel therapies. A key to this is a better molecular and genetic understanding of the causes underlying ALS phenotypes. Through parallel genetic disease model screens in Drosophila, we found that mutations in phospho-lipase D (PLD), and at least six components in its upstream intracellular pathway, serve to suppress and control the toxic impact of TDP-43 and FUS mutations in the nervous system, indicating that the PLD pathway is a significant potential ALS target. This signaling pathway is multifunctional and has been linked to cancer as well as other neurodegenerative diseases. We also identified the VEGF/PDGF growth factor pathway (Pvf-Pvr in Drosophila), a likely upstream signaling input to PLD, as an potent modulator of ALS phenotypes. Deeper analysis to understand the specific mechanisms underlying the impact of PLD and VEGF/PDGF on ALS phenotypes is essential before they can be pursued as future therapeutic targets. Here, we propose to further leverage the strengths of Drosophila to confirm that changes in the PLD pathway modulation can prevent progressive, adult-onset neuromuscular failure. Depending on the results we will obtain, this exploratory project (R21) may form the basis to justify future analysis under R01-based mechanism.