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

VASALLI, F.; ALFIERI, J.; DUARTE, L. A.; DE LANDETA, A.B.; KATCHE, C.; PÍREZ, N.; MULLER IGAZ, L.

Trieste

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

International Centre for Genetic Engineering and Biotechnology

Mislocalization and aggregation of the nuclear protein TDP-43 are hallmark features ofthe neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporaldementia (FTD). We have shown in mice that inducible overexpression of a cytoplasmicallylocalizedform of TDP-43 (TDP-43-ΔNLS) in forebrain neurons recapitulates severalfeatures 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 ourmouse model. Using gene expression data from microarray studies in TDP-43-ΔNLS braintissue 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 werecorroborated at the protein level by immunofl uorescence analysis of TDP-43-ΔNLS corticaland hippocampal tissue. We corroborated by immunoblot that Zif268 protein levels aredramatically decreased in TDP-43-ΔNLS brain, while exposure to a behavioural challengesuch as an open fi eld does not elicit proper PRG induction in these mice. We complementthis data using immunoblot analysis and investigate in TDP-43 mice the protein levels ofBDNF, 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 calciumimaging experiments in the antennal lobe olfactory receptor neurons. Our results fromtransgenic mice indicate that abnormal PRG protein levels may underlie the behaviouralabnormalities in TDP-43 related pathologies.