DEVELOPMENT OF AN ADENO-ASSOCIATED VIRUS (AAV)-BASED MODEL TO STUDY TDP-43 PATHOPHYSIOLOGY IN RODENTS

DORMAN G; ALFIERI JA; MEDINA JH; IGAZ LM

Congreso; XXVI Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia (SAN); 2011

TAR DNA-binding protein 43 (TDP-43) is a protein involved in diverse cellular functions and was recently identified as a major disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. To study the pathophysiological role of TDP-43 in vivo, we developed a novel model using Adeno-associated virus (AAV)-based vectors to express wild-type TDP-43, a carboxyl-terminal fragment or TDP-43 variants with cytoplasmic or nuclear localization. Leer fonéticamente This project aims to evaluate in the rodent brain whether overexpression of different TDP-43 species leads to disease-related pathological features (including TDP-43 aggregation, ubiquitination, hyperphosphorylation and cleavage). Our goal is to analyze if expression of any of these TDP-43 species results in neurodegeneration, and to study the potential effect of hippocampal or cortical TDP-43 overexpression in cognitive function (i.e. learning and memory) by behavioral analysis but also at biochemical level by assessing changes in plasticity-related pathways. The results of this project might provide more knowledge regarding the pathogenic mechanisms underlying TDP-43 proteinopathies, which hopefully will help the development of new and more effective therapies for these disorders.