TDP-43 TRANSGENIC MOUSE MODELS DISPLAY ALTERED BRAIN POLYSOMAL PROFILES

LUCHELLI L; AVALE ME; IGAZ LM

Huerta Grande, Cordoba, Argenitna

Congreso; XXIX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2014

Sociedad Argentina de Investigación en Neurociencias (SAN)

TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein in a group of neurodegenerative diseases including Frontotemporal Dementia (FTD) and amyotrophic lateral sclerosis (ALS). In addition, TDP-43 is a nucleic acid-binding protein that regulates multiple aspects on mRNA metabolism. We are studying in vivo the intrinsic properties and physiological role of TDP-43 to define its involvement in neurodegenerative disease. To do this, we are using two different models: (1) Transgenic mice overexpressing human wild-type TDP-43 protein (hTDP-43-WT) or a cytoplasmically localized form (hTDP-43-NLS) and (2) TDP-43 knock-down using a lentiviral-based shRNA approach. To investigate if TDP-43 has any participation in regulating active translation and therefore in maintaining protein levels we performed subcellular fractionation of brain areas by sucrose gradient centrifugation. The polysome profile of hTDP-43-WT brains was significantly altered by a shift towards light fractions as compared to wild-type littermates, indicating a decrease in global mRNA translation. That change correlates with a shift of TDP-43 protein. Preliminary analysis of hTDP-43-NLS cortical polysome profiles suggests changes in mRNA levels from all gradient fractions. These results provide initial evidence for a potential role of TDP-43 regulation of global mRNA translation.