Differential roles of the ubiquitin proteasome system (UPS) and autophagy in the clearance of soluble and aggregated TDP-43 species

Abstract

TARDBP (TDP-43) is the major pathological protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Large TDP-43 aggregates decorated by degradation adaptor proteins are seen in the cytoplasm of remaining neurons in patients post mortem. TDP-43 accumulation, and ALS-linked mutations within degradation pathways, implicates failed TDP-43 clearance as a primary disease mechanism. Here we report the differential roles of the ubiquitin proteasome system (UPS) and autophagy in the clearance of TDP-43. We have investigated the effects of UPS and autophagy inhibitors on the degradation, localisation and mobility of soluble and insoluble TDP-43. We find that soluble TDP-43 is degraded primarily by the UPS, while aggregated TDP-43 clearance requires autophagy. Cellular macroaggregates, which recapitulate many pathological features of patient aggregates, are reversible when both the UPS and autophagy are competent. Their clearance involves the autophagic removal of oligomeric TDP-43. We speculate that in addition to age-related decline, a second hit in the UPS or autophagy pathways drives the accumulation of TDP-43 in ALS and FTD. Therapies for clearing excess TDP-43 should therefore be targeted to a combination of these pathways.