UPS delivers TDP-43 for degradation Free

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are characterised by the deposition of pathological protein aggregates of TAR DNA-binding protein (TARDBP; hereafter referred to as TDP-43). The cytoplasmic accumulation of TDP-43 has been linked to its toxicity and might be due to a clearance failure. In the cell, two main degradation pathways are responsible for protein removal, the ubiquitin proteasome system (UPS) and macroautophagy (hereafter referred to as autophagy), but their relative contribution to TDP-43 proteostasis is unknown. On page 1263, Christopher Shaw and co-workers now investigate how the degradation of TDP-43 is regulated in cellular models of ALS and FTD that are based on cell lines expressing different TDP-43 constructs that recapitulate its localisation and cleavage profiles in the disease state. By using inhibitors of either UPS or autophagy, the authors find that soluble TDP-43 is degraded primarily by the UPS, whereas the clearance of TDP-43 macroaggregates additionally requires autophagy. Interestingly, when both UPS and autophagy are functional in the cell, large cellular TDP-43 aggregates that mimic those seen in disease can be cleared from cells. This suggests that enduring impairment of UPS and/or autophagy promotes the accumulation of misfolded TDP-43 in ALS and FTD patients, in addition to the overall decline in the activity of these pathways that occurs during normal aging. On the basis of these results, the authors propose the combined activation of UPS and autophagy as a valuable therapeutic strategy to prevent TDP-43 accumulation in order to combat its toxic effects in ALS and FTD.