TDP-43 overexpression affects global brain translation

CHARIF, SE; BLAUSTEIN, M.; COLMAN-LERNER, A.; VILA, A; MULLER IGAZ, L.

Villa Carlos Paz, Cordoba

Congreso; XXXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2019

Sociedad Argentina de Investigación en Neurociencias (SAN)

TDP-43 is a RNA-bindingprotein that, amongst other functions, participates in mRNA metabolism, and itis a major component of inclusions observed in neurodegenerative diseases likefrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Previousresults from our lab showed a decrease in global mRNA translation as comparedto wild-type animals, revealed by polysome profiling of brain cortex fromhTDP-43 expressing mice. To further understand the role of TDP-43 in mRNA and proteinmetabolism, we used a combined approach with animal and cellular models. Applicationof SUNSET method (which assesses ongoing translation) in brain slices from controland hTDP-43-ΔNLS expressing mice revealed a decrease in puromycinincorporation in brain cortex cells of ΔNLSmice when compared to control animals. Complementary immunoblot analysis corroboratesthat puromycin is actively incorporated during translation of new proteins. TheUnfolded Protein Response (UPR) is a major cellular process that also regulatestranslation. To assess in vitro howTDP-43 modulates the UPR, HEK293 cells were transfected with TDP-43 variants andtreated with vehicle or ER stress inducers. We are currently analyzing ATF4 andATF6 pathways; preliminary data corroborate that MG132 induces ATF6 cleavageand ATF4 protein levels. These results suggest that dysregulation of TDP-43might alter global translation and that cytotoxic effects in FTD/ALS might be dueto alterations in proteostasis by TDP-43.