D-083 | Expression of human TDP-43 leads to behavioral abnormalities and altered neuronal activity in a Drosophila model of ALS/FTD.

Disorders of the Nervous System
Author: Azul Denise Galo | Email: azu.galo@gmail.com

Azul Denise Galo^1°2°, Lautaro Duarte^3°, Florencia Vassallu^1°2°,  Vinicius Bongiovanni^1°2°, Pablo Bochicchio^4°, Diego Hernán Bodin^4°, Nicolas Pírez^3°,  Maximiliano Katz^1°2°, Lionel Muller Igaz^1°2°

^1° Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas. Buenos Aires, Argentina.
^2° CONICET – Universidad de Buenos Aires. Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay). Buenos Aires, Argentina.
^3° Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Departamento de Fisiología, Biología Molecular y Celular and CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina
^4° Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Departamento de Biodiversidad y Biología Experimental, Laboratorio de Neuroetología de Insectos. Buenos Aires, Argentina

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 studied. We have shown in mice that inducible overexpression of human TDP-43 (hTDP-43) in forebrain neurons recapitulates several features of TDP-43 proteinopathies. In this study, we are using Drosophila models expressing hTDP-43-WT to evaluate a) behavioral phenotypes in flies expressing hTDP-43 in the mushroom bodies (MBs) and b) evoked neuronal activity through calcium imaging experiments in the antennal lobe olfactory receptor neurons (ORNs). Using a custom-made behavioural tracking software, we assessed locomotor activity (open field test) in non-transgenic Control or MB-expressing hTDP-43 flies. In young hTDP-43 flies, both males and females showed decreased distance travelled respect to Controls, while aged flies revealed a sexually dimorphic phenotype (increased distance in males and no differences with controls in females). Using the calcium indicator Gcamp6f, we showed that ORN activity from hTDP-43 flies is decreased respect to controls. Our results from transgenic flies underscore the utility of using multiple, phylogenetically distant organisms to model complex human neurological diseases, including ALS/FTD.