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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 "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.

SUBMITTER: Streit L 

PROVIDER: S-EPMC9485239 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Stress induced TDP-43 mobility loss independent of stress granules.

Streit Lisa L   Kuhn Timo T   Vomhof Thomas T   Bopp Verena V   Ludolph Albert C AC   Weishaupt Jochen H JH   Gebhardt J Christof M JCM   Michaelis Jens J   Danzer Karin M KM  

Nature communications 20220919 1

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 mobilit  ...[more]

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