‘PathensTDP’. Defining the role of hnRNP proteins in enhancing TDP-43 pathology

Heterogeneous ribonucleoproteins (hnRNPs) are a family of RNA-binding proteins (RBPs) implicated in several steps of RNA metabolism, including transcription, pre-mRNA splicing, mRNA transport and turnover. In particular, TDP-43 is a member of this family that was discovered in 2006 as the major component of ubiquitin-positive inclusions in brain tissues from ALS and FTLD patients. Since then, many additional RBPs have been found to play a role in neurological disorders. Unfortunately, these proteins do not represent good therapeutic targets due to the multitude of functions they play in cells. However, the identification of key transcripts regulated by their overexpression/depletion may represent a valid alternative. In the PathensTDP project we have focused on five hnRNPs (DAZAP1, hnRNPD, hnRNPK, hnRNPQ and hnRNPU) that we previously identified as strong functional modulators of TDP-43 activity in Drosophila and human cells. Our preliminary data following whole transcriptome analysis of neuronal-like cells depleted for each hnRNP, including TDP-43, have shown the presence of several commonly regulated mRNAs that could play an important role in modulating TDP-43 pathology. To assess the therapeutic implications of these candidate genes, we will now examine their effects on the synaptic plasticity/death-signalling pathways both in cellular and animal models.