Clearance mechanisms of aggregated TDP-43 responsible for ALS/FTD diseases

Increasing biochemical and genetic evidence have suggested that Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two related neurodegenerative diseases, with a continuous clinical spectrum. Even if the neuronal population affected may differ between ALS and FTD, a common feature is the mislocalization and aggregation of the TAR DNA binding protein 43 (TDP-43), in affected cells. TDP-43 aggregates contain C-terminal TDP-43 fragments of 35\u2009kDa (TDP-35) and 25\u2009kDa (TDP-25), that are highly aggregation-prone, and are thought to be neurotoxic. We have investigated the role of protein quality control (PQC) system and extracellular vesicles in the clearance of TDP-43 and its C-terminal fragments. We have demonstrated that all TDP-43 species are cleared by proteasome, but TDP-25 impairs autophagy. We found that the routing of TDP fragments to proteasome or to autophagy decreased the accumulation of both TDP43 fragments, possibly reducing their toxicity. Moreover, we observed that all TDP-43 species are secreted in EVs, mainly in MVs