Stress induced TDP-43 mobility loss independent of stress granules
Lisa Streit, Timo Kühn, Thomas Vomhof, Verena Bopp, Albert C. Ludolph, Jochen H. Weishaupt, J. Christof M. Gebhardt, Jens Michaelis, Karin M. Danzer
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 "crucibles" 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. This work provides insights into the aggregation of TDP-43 in living cells and provide evidence suggesting that TDP-43 oligomerization and aggregation takes place in the cytoplasm separate from SGs.