IFIBIO HOUSSAY   25014
INSTITUTO DE FISIOLOGIA Y BIOFISICA BERNARDO HOUSSAY
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
TDP-43 transgenic mouse models display altered brain polysomal profiles
Autor/es:
LUCHELLI LUCIANA; MULLER IGAZ LIONEL
Reunión:
Congreso; Congreso de la sociendad de Neurociencias Argentina; 2014
Resumen:
 TAR DNA-binding protein 43(TDP-43), encoded by the TARDBP gene, has been identified as the majorpathological protein in a group of neurodegenerative diseases including FrontotemporalDementia (FTD) and amyotrophic lateral sclerosis (ALS). In addition, TDP-43 isa nucleic acid-binding protein that regulates multiple aspects on mRNAmetabolism. We are studying in vivothe intrinsic properties and physiological role of TDP-43 to define itsinvolvement in neurodegenerative disease. To do this, we are using twodifferent models: (1) Transgenic mice overexpressing human wild-type TDP-43 protein (hTDP-43-WT) or a cytoplasmicallylocalized form (hTDP-43-ΔNLS) and (2) TDP-43 knock-downusing a lentiviral-based sh-RNA approach. To investigate if TDP-43 has anyparticipation in regulating active translation and therefore in maintainingprotein levels we performed subcellular fractionation of brain areas by sucrosegradient centrifugation. The polysome profile of hTDP-43-WT brains wassignificantly altered by a shift towards light fractions as compared towild-type littermates, indicating a decrease in global mRNA translation. Thatchange correlates with a shift of TDP-43 protein. Preliminary analysis of hTDP-43-ΔNLScortical polysome profiles suggests changes in mRNA levels from all gradientfractions. These results provide initial evidence for a potential role ofTDP-43 regulation of global mRNA translation.