Assessing alternative splicing of TDP-43 target genes in the brain of conditional mouse models of FTD/ALS

LUCIANA E. GIONO; LUCIANA LUCHELLI; LIONEL MULLER IGAZ; ANA FISZBEIN; ALBERTO R. KORNBLIHTT

Buenos Aires

Congreso; 2nd FALAN Congress; 2016

FALAN - SAN

Alterations at the level of RNA binding proteins (RBPs) have been recently described as a crucial event in manydisorders, playing a central role in neurodegenerative disease. One of the main RBPs involved in these processes is TDP-43, particularly in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In these and other TDP- 43 proteinopathies, the disruption of protein homeostasis and RNA emerges as a convergent molecular feature. TDP-43 is emerging as a key protein involved in multiple integrated regulatory pathways of RNA metabolism; however, its specific functions in the nervous system are just beginning to be explored. Here, we aim to study in vivo the role of TDP- 43 in the regulation of alternative splicing in the brain, using two novel animal models based on the conditional 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 behavioral deficits and progressive neurodegeneration. We are using radioactive RT-PCR to determine splicing effects on TDP-43 target genes, including Sort1 and Poldip3/Skar, in the hippocampus and prefrontal cortex of TDP-43 transgenic mice. These results will contribute to address in vivo the pathogenic mechanisms underlying TDP-43 proteinopathies.