Studying the Effect of TDP-43 Proteinopathy on Frontotemporal Dementia-Related Behaviors in Drosophila melanogaster

The RNA-binding protein TDP-43 has been linked to Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) both at the level of pathology and as a causative factor. Specifically, 97% of ALS and 45% of FTD patients exhibit cytosolic aggregates containing TDP-43, and 4-5% of ALS patients harbor mutations within TARDBP, the gene encoding TDP-43 (Bott, Radke, Stephens, & Kramer, 2014). To develop a Drosophila model of TDP-43-induced FTD, we expressed TDP-43 in Kenyon cells, a group of neurons within the mushroom bodies, which are functionally analogous to human hippocampal neurons, and are believed to be responsible for learning and memory in Drosophila (Akalal et al., 2006; Heisenberg, 2003; Muller, 1996). We found that the expression of human TDP-43 transgenes in Drosophila causes the formation of TDP-43 aggregates and axonal degeneration in the mushroom bodies, similar to FTD pathology. To determine whether TDP-43 overexpression in mushroom bodies causes learning and memory deficits, we used an oviposition-based memory assay. Normally, wild-type Drosophila show depressed egg laying when exposed to endoparasitoid wasps that will infect and kill their progeny (Carton, Boulétreau, van Alphen, & van Lenteren, 1986; Schlenke, Morales, Govind, & Clark, 2007), and this response is maintained for several days even after wasps are removed. This indicates that exposed flies form a memory of the wasp threat, allowing study into manipulations that abolish memory (Kacsoh, Bozler, Ramaswami, & Bosco, 2015). Our experiments show that similar to controls, flies expressing human wild-type or mutant TDP-43 responded to the wasp threat by laying fewer eggs, indicating that TDP-43 proteinopathy does not result in impaired fear response in young flies. We were not able to recapitulate previous work showing memory of wasp exposure in wild type flies, and thus could not assess any potential effect of TDP-43 on that memory. Interestingly, our data reveal that unexposed flies expressing the human G298S mutant TDP-43 lay significantly more eggs that controls or flies expressing wild-type human TDP-43 suggesting that TDP-43 may interfere with normal egg-laying behavior