BIOCHEMICAL EVIDENCE FOR ALTERED PROTEIN LEVELS OF PLASTICITY-RELATED GENES IN INDUCIBLE TDP-43- ΔNLS TRANSGENIC MICE.

DE LANDETA AB; ALFIERI JA; KATCHE C; IGAZ LM

Mar del Plata

Congreso; XXXII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2017

Mislocalizationand aggregation of the nuclear protein TDP-43 are hallmark features of theneurodegenerative diseases amyotrophic lateral sclerosis (ALS) andfrontotemporal dementia (FTD). We have shown in mice that inducibleoverexpression of a cytoplasmically-localized form of TDP-43 (TDP-43-ΔNLS) inforebrain neurons evokes neuropathological and behavioral changes thatrecapitulate several features of TDP-43 proteinopathies. Here, we focus on plasticity-related genes(PRGs) which are key for normal cognition, a functionaffected in both human disease and our mouse model. Using gene expression datafrom microarray studies in TDP-43-ΔNLSbrain tissue as a springboard, we identified decreased mRNA levels of Zif268, c-fosand Arc, three PRGs critically involved in cognitive function and neuralplasticity. These changes were corroborated and expanded by immunofluorescenceanalysis of TDP-43-ΔNLScortical and hippocampal tissue. Here, we complement and extend this data usingimmunoblot analysis from cortex and hippocampus of TDP-43 mice, and investigatein TDP-43 mice the protein levels of BDNF, a neurotrophin with key functions inplasticity. We found that Zif268 protein levels are dramatically decreased in TDP-43-ΔNLS brain,while exposure to a behavioural challenge such as an open field does not elicitproper PRG induction in these mice. Remarkably, BDNF protein levels areincreased in TDP-43-ΔNLSbrain, suggesting a compensatory mechanism involving this neurotrophin. Theseresults indicate that abnormal PRG protein levels may underlie the behaviouralabnormalities in TDP-43 related pathologies.