Endolysosomal pathway activity protects cells from neurotoxic TDP-43

Abstract

The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP-43). Using a yeast model for TDP-43 pro-teinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP-43. This clearance occurred via TDP-43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy. In line with its dominant role in the clearance of TDP-43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP-43. In contrast, enhanced autophagy contributed to TDP-43 cyto-toxicity, despite being involved in TDP-43 degradation. TDP-43’s interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP-43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP-43-associated diseases.