Stress induced TDP-43 mobility loss independent of stress granules

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 “bioreactors” 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.