Although ubiquitination targets TDP-43 aggregates for degradation, TDP-43 begins to accumulate in the cytoplasm, suggesting that additional perturbance in either the ubiquitin-proteasome system or the autophagy pathway can facilitate the accumulation of TDP-43 in ALS and FTD-U19. The gene discussed is TARDBP; the disease is amyotrophic lateral sclerosis.