TDP-43 is a ubiquitously expressed nucleic acid-binding protein regulating transcription and different steps of RNA metabolism, including RNA splicing, alternative polyadenylation, transport and translation. TDP-43 binds to thousands of RNAs in the brain and is found in insoluble protein aggregates in neurons and glia of some patients with neurodegenerative diseases.

More than 50 missense mutations in the TARDBP gene, encoding TDP-43, have been found in patients with amyotrophic lateral sclerosis (ALS, which affects motor neurons) and frontotemporal lobar degeneration (FTLD, which affects cortical neurons). The mutations in the TARDBP gene contribute to neurological diseases both through loss of function and gain of function mechanisms. However, it is still unclear what the main driver(s) of neuronal degeneration are. Our lab has previously shown that p53-mediated apoptosis contributes to neuronal cell death in the mouse neocortex and in human induced pluripotent stem cell (hiPSC)-derived cortical neurons overexpressing wild-type or expressing mutant TDP-43. Genetic deletion of Trp53 or pharmacological inhibition p53 rescued apoptosis in vivo in mice and in vitro in hiPSC-derived cortical neurons.

The aim of my project is to further investigate the consequences of TARDBP mutation on hiPSC-derived cortical neurons and the effect of p53 inhibition. The analysis of RNA-seq and tandem mass spectroscopy data will allow to unveil the molecular impact of TARDBP mutations in hiPSC-derived neurons and the mechanisms of how the pharmacological treatment reduces cell death. Moreover, even though FTLD is a late-onset disease, this study will enable us to understand whether TARDBP mutations have impacts on normal differentiation and gene expression by cortical neurons which would imply a neurodevelopmental aspect to TDP-43 induced disease.