Stress induced TDP-43 mobility loss independent of stress granules

Abstract

TAR DNA binding protein 43 (TDP-43) is closely related to the pathogenesis of amyotrophic lateral sclerosis (ALS) and translocates to stress granules (SGs). The role of SGs as aggregation-promoting 'bioreactor' for TDP-43, however, is still under debate. We analyzed TDP-43 mobility and localization under different stress and recovery conditions using live cell single-molecule tracking and super-resolution microscopy. Besides reduced mobility within SGs, a stress induced decrease of TDP-43 mobility in the cytoplasm and the nucleus was observed. Stress removal led to a recovery of TDP-43 mobility, which strongly depended on the stress duration. Stimulated-emission depletion microscopy (STED) and tracking and localization microscopy (TALM) revealed not only TDP-43 substructures within stress granules but also numerous patches of slow TDP-43 species throughout the cytoplasm. The data provide new insights into the aggregation of TDP-43 in living cells and provide evidence suggesting that TDP-43 oligomerization takes place in the cytoplasm separate from SGs.

Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates

“…40 However, other work has suggested that aggregation occurs outside rather than inside stress granules and has proposed that stress granules might protect against aggregation. 24,[41][42][43][44][45][46] These disparate results have made it difficult to come to any general conclusions about the role of stress granule condensates in TDP-43 aggregation.…”