The unexplored posttranslational modification (SUMOylation) of TDP-43 affects aggregate formation and localisation

Cytoplasmic aggregates of TDP-43 are a hallmark feature of ALS. The mislocalisation of TDP-43 from the nucleus into the cytoplasm appears to be detrimental for neuron survival. For TDP-43 to localize into the right compartment, it undergoes post-translational modifications (PTMs). We demonstrate for the first time that one of these PTM-pathways (SUMOylation) is critical for the localization of TDP-43 aggregates, nerve growth and cell-viability. In this proposal we aim to assess the implications of SUMOyation in vivo and in patient tissue. Importantly, the SUMOylation pathway has been recently demonstrated to be a promising therapeutic target in other neurodegenerative diseases.