Human TDP-43 drives behavioral and neuronal alterations in a Drosophila model of ALS/FTD

Alterations of the nuclear protein TDP-43 are hallmark features of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 is an evolutionary conserved protein with multiple cellular functions, most notably related to RNA metabolism. However, its role in the regulation of neuronal activity is less known. In this study, we use a Drosophila melanogaster model express hTDP-43-WT to evaluate a) behavioural phenotypes in flies expressing hTDP-43 in the mushroom bodies (MBs) and b) evoked neuronal activity through PKA and ERK Separation of Phases-based Activity Reporters of Kinase (SPARK) experiments in the antennal lobe olfactory receptor neurons (ORNs). Using a custom-made behavioural tracking software, we assessed locomotor activity (open field test) in Control and MB-expressing hTDP-43 flies. In young hTDP-43 female flies (10-12 days old), we observed decreased distance travelled compered to controls. In addition, we demonstrated that hTDP-43 expression induces PKA and ERK phosphorylation in MB and ORNs, indicating activation of two signaling pathways critical for neuronal function and plasticity. Our results from transgenic flies underscore the utility of using multiple, phylogenetically distant organisms to model complex human neurological diseases, including ALS/FTD.