Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons. TAR DNA-binding protein (TDP-43) is an RNA and DNA binding protein that has been implicated in ALS, both as a causative factor and at the level of pathology. Although TDP-43 has been shown to play a key role in RNA metabolism, its mechanism is not fully understood. Specifically, evidence has shown that TDP-43 binds TG-rich sequences within RNA targets. In the context of disease, this binding can lead to alterations in splicing and/or proper regulation of its targets, and is partially responsible for the neurotoxicity that is associated with ALS. A 4-aminoquinoline analog (i.e. AAQ-2) has been shown to inhibit the binding of TDP-43 to TG oligonucleotides. To evaluate the effect of this small molecule in vivo, we administered AAQ probes to larvae expressing wild-type or mutant TDP-43 in motor neurons (D42 GAL4>TDP-43). Our experiments show that feeding of AAQ-2, but not a structurally similar negative control (AAQ-9), rescues the lethality caused by overexpression of TDP-43 in motor neurons. Additionally, AAQ-2 feeding also leads to improved locomotor function of larvae, as well as increased lifespan of flies overexpressing both wild-type and mutant TDP-43. In exploring the role of TDP-43-associated proteins in mediating the protective effect of AAQ-2 in motor neurons, we find that rescue of TDP-43-induced neurotoxicity by AAQ-2 is dependent in Fragile X Mental Retardation Protein (FMRP) in a TDP-43 variant-dependent manner. Currently, experiments are being performed to determine the effect of AAQ-2 on the solubility of full-length TDP-43 and its cleaved C-terminal fragment within motor neurons. These results provide insight into the role of TDP-43 in RNA metabolism, as well as suggest a possible therapeutic strategy for TDP-43-based ALS and related neurodegenerative diseases.