4-aminoquinoline analogs rescue neurotoxicity in a Drosophila model of ALS based on TDP-43. Alyssa Coyne¹, Marilyn Roy², Ivy Lin², Joel Cassel⁴, Mark McDonnell⁴, Allen Reitz⁴, Daniela Zarnescu^2,3. 1) Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA; 2) Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA; 3) Department of Neurology, University of Arizona, Tucson, AZ 85721, USA; 4) Biopharma, LLC, Pennsylvania Biotechnology Center, Doyleston, PA 18902, USA.

   TAR DNA-binding protein (TDP-43) is an RNA and DNA binding protein that has been implicated in Amyotrophic Lateral Sclerosis (ALS). ALS is a progressive neurodegenerative disease for which there is currently no cure. Because the mechanisms behind TDP-43 action are poorly understood, it is difficult to pinpoint therapeutic targets. Increasing evidence however, supports a role in RNA metabolism and recently, TDP-43 was shown to directly bind (TG)_n sequences. The high affinity binding of TDP-43 to TG oligonucleotides is inhibited by 4-aminoquinoline (AAQ) probes, which also lead to increased caspase cleavage of TDP-43 in vitro. To test their effect in vivo, we fed AAQ probes to larvae expressing wild-type and mutant TDP-43 in motor neurons (D42>TDP-43). These experiments show that AAQ probes but not a structurally related negative control rescue the lethality induced by TDP-43 overexpression in motor neurons. Furthermore, AAQs mitigate defects in larval locomotor activity due to TDP-43 neurotoxicity. Current experiments are aimed at determining the physiological effects of AAQs in vivo, using a battery of neuroanatomical and behavioral phenotypes caused by TDP-43 overexpression in motor neurons or glia. Our initial results provide novel insights into the physiological role of TDP-43s association with nucleic acids and suggest a novel therapeutic strategy for TDP-43 based ALS.