ASSESSING ALTERNATIVE SPLICING OF TDP-43 TARGET GENES IN THE BRAIN OF CONDITIONAL MOUSE MODELS OF FTD/ALS.

LUCHELLI L; GIONO L; IGAZ LM; FISZBEIN A; KORNBLIHTT AR

Buenos Aires

Congreso; 2nd FALAN (Federation of Latin American and Caribbean Neurosciences) Congress; 2016

FALAN (Federation of Latin American and Caribbean Neurosciences)

Alterations at the level of RNA binding proteins (RBPs)have been recently described as a crucial event in many disorders, playing a centralrole in neurodegenerative disease. One of the main RBPs involved in theseprocesses is TDP-43, particularly in amyotrophic lateral sclerosis (ALS) andfrontotemporal dementia (FTD). In these and other TDP-43 proteinopathies, thedisruption of protein homeostasis and RNA emerges as a convergent molecularfeature. TDP-43 is emerging as a key protein involved in multiple integratedregulatory pathways of RNA metabolism; however, its specific functions in thenervous system are just beginning to be explored. Here, we aim to study in vivothe role of TDP-43 in the regulation of alternative splicing in the brain,using two novel animal models based on theconditional neuronal overexpression in the mouse forebrain of either nuclear (hTDP-43 WT) or cytoplasmic (hTDP-43-ΔNLS) forms of human TDP-43. We show here that these mice recapitulate key aspects of FTLD/ALS, including behavioraldeficits and progressive neurodegeneration. We are using radioactive RT-PCR to determine splicing effects on TDP-43target genes, including Sort1 and Poldip3/Skar, in the hippocampus andprefrontal cortex of TDP-43 transgenic mice. These results will contribute to address in vivo the pathogenicmechanisms underlying TDP-43 proteinopathies.