D-083 | Expression of human cytoplasmic 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 and frontotemporal dementia. TDP-43 is an evolutionary conserved nuclear 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 expression of cytoplasmic human TDP-43 (hTDP-43-DNLS) in forebrain neurons recapitulates several features of TDP-43 proteinopathies. In this study, we used Drosophila models expressing hTDP-43-ΔNLS to evaluate a) locomotion in flies expressing hTDP-43-DNLS in the mushroom bodies (MBs); b) evoked neuronal activity through calcium imaging experiments in the antennal lobe (AL) olfactory receptor neurons (ORNs) and c) accumulated neuronal activity in MBs and ALs using the calcium reporter CalexA. Using a custom-made behavioural tracking software, we assessed locomotor activity in non-transgenic Control or MB-expressing hTDP-43-ΔNLS flies. Both males and females mutant flies showed altered distance travelled respect to Controls, although with different age-dependent phenotypes. Using the calcium indicator Gcamp6f, we showed that ORN activity from hTDP-43-ΔNLS flies was not altered, while the CalexA experiments revealed reduced activity in both ALs and MBs. Our results underscore the utility of using multiple, phylogenetically distant organisms to model complex human neurological diseases.