Stress induced TDP-43 mobility loss independent of stress granules

Lisa Streit, Timo Kuhn, Thomas Vomhof, Verena Bopp, Albert C. Ludolph, Jochen H. Weishaupt, J. Christof M. Gebhardt, Jens Michaelis () and Karin M. Danzer ()
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Lisa Streit: Ulm University
Timo Kuhn: Ulm University
Thomas Vomhof: Ulm University
Verena Bopp: University Clinic
Albert C. Ludolph: University Clinic
Jochen H. Weishaupt: University Clinic
J. Christof M. Gebhardt: Ulm University
Jens Michaelis: Ulm University
Karin M. Danzer: University Clinic

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32939-0

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