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bioRxiv · 10.1101/2022.02.28.482242

Stress induced TDP-43 mobility loss independent of stress granules

Streit, L.·Kuhn, T.·Vomhof, T.·Ludolph, A. C.·Weishaupt, J. H.·Gebhardt, J. C. M.·Michaelis, J.·Danzer, K. M.
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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 "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.

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Streit, L., Kuhn, T., Vomhof, T., Ludolph, A. C., Weishaupt, J. H., Gebhardt, J. C. M., Michaelis, J., Danzer, K. M.. 2022-02-28. Stress induced TDP-43 mobility loss independent of stress granules. https://doi.org/10.1101/2022.02.28.482242

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