Plasticity-related genes mRNA and protein levels are altered in inducible TDP-43-ΔNLS transgenic mice: implications for TDP-43 proteinopathies

VASSALLU, FLORENCIA; ALFIERI, J; DUARTE, L; DE LANDETA, AB; KATCHE C; PIREZ N; MULLER IGAZ, L

Congreso; 1st biennial conference on TDP-43 function and dysfunction in disease; 2023

Mislocalization and aggregation of the nuclear protein TDP-43 are hallmark features of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We have shown in mice that inducible overexpression of a cytoplasmically-localized form of TDP-43 (TDP-43-ΔNLS) in forebrain neurons recapitulates several features of TDP-43 proteinopathies. Here, we focus on plasticity-related genes (PRGs) which are key for normal cognition, a function affected in both human disease and our mouse model. Using gene expression data from microarray studies in TDP-43-ΔNLS brain tissue as a springboard, we identifi ed decreased mRNA levels of Zif268, c-fos and Arc, PRGs critically involved in cognitive function and neural plasticity. These changes were corroborated at the protein level by immunofl uorescence analysis of TDP-43-ΔNLS cortical and hippocampal tissue. We corroborated by immunoblot that Zif268 protein levels are dramatically decreased in TDP-43-ΔNLS brain, while exposure to a behavioural challenge such as an open fi eld does not elicit proper PRG induction in these mice. We complement this data using immunoblot analysis and investigate in TDP-43 mice the protein levels of BDNF, a neurotrophin with key functions in plasticity. We are also using Drosophila TDP-43 models to evaluate in vivo evoked and spontaneous neuronal activity through calcium imaging experiments in the antennal lobe olfactory receptor neurons. Our results from transgenic mice indicate that abnormal PRG protein levels may underlie the behavioural abnormalities in TDP-43 related pathologies.