title: Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species.
abstract: TAR DNA-binding protein (TDP-43, also known as TARDBP) is the major pathological protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Large TDP-43 aggregates that are decorated with degradation adaptor proteins are seen in the cytoplasm of remaining neurons in ALS and FTD patients post mortem. TDP-43 accumulation and ALS-linked mutations within degradation pathways implicate failed TDP-43 clearance as a primary disease mechanism. Here, we report the differing roles of the ubiquitin proteasome system (UPS) and autophagy in the clearance of TDP-43. We have investigated the effects of inhibitors of the UPS and autophagy on the degradation, localisation and mobility of soluble and insoluble TDP-43. We find that soluble TDP-43 is degraded primarily by the UPS, whereas the clearance of aggregated TDP-43 requires autophagy. Cellular macroaggregates, which recapitulate many of the pathological features of the aggregates in patients, are reversible when both the UPS and autophagy are functional. Their clearance involves the autophagic removal of oligomeric TDP-43. We speculate that, in addition to an age-related decline in pathway activity, a second hit in either the UPS or the autophagy pathway drives the accumulation of TDP-43 in ALS and FTD. Therapies for clearing excess TDP-43 should therefore target a combination of these pathways.
authors.affiliation: Institute of Psychiatry, King's College London, 1 Windsor Walk, Denmark Hill, London SE5 8AF, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Scotter
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: Agnes L
authors.initials: AL
authors.lastname: Nishimura
authors.forename: Youn-Bok
authors.initials: YB
authors.lastname: Lee
authors.forename: Han-Jou
authors.initials: HJ
authors.lastname: Chen
authors.forename: Hazel
authors.initials: H
authors.lastname: Urwin
authors.forename: Valentina
authors.initials: V
authors.lastname: Sardone
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Mitchell
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
mesh_terms: D001343:Autophagy; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D066329:Protein Aggregates; D059748:Proteolysis; D057177:TDP-43 Proteinopathies / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D066329:Protein Aggregates; D046988:Proteasome Endopeptidase Complex
keywords: ALS; Aggrephagy; Autophagy; Proteasome; TDP-43; UPS