Stress granule assembly can facilitate but is not required for TDP-43 cytoplasmic aggregation

Nikita Fernandes, Luke Nero, Shawn M. Lyons, Pavel Ivanov, Telsa M. Mittelmeier, Timothy A. Bolger, J. Ross Buchan

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Stress granules (SGs) are hypothesized to facilitate TAR DNA-binding protein 43 (TDP-43) cytoplasmic mislocalization and aggregation, which may underly amyotrophic lateral sclerosis pathology. However, much data for this hypothesis is indirect. Additionally, whether P-bodies (PBs; related mRNA-protein granules) affect TDP-43 phenotypes is unclear. Here, we determine that induction of TDP-43 expression in yeast results in the accumulation of SG-like foci that in >90% of cases become the sites where TDP-43 cytoplasmic foci first appear. Later, TDP-43 foci associate less with SGs and more with PBs, though independent TDP-43 foci also accumulate. However, depleting or over-expressing yeast SG and PB proteins reveals no consistent trend between SG or PB assembly and TDP-43 foci formation, toxicity or protein abundance. In human cells, immunostaining endogenous TDP-43 with different TDP-43 antibodies reveals distinct localization and aggregation behaviors. Following acute arsenite stress, all phospho-TDP-43 foci colocalize with SGs. Finally, formation of TDP-43 cytoplasmic foci following low-dose chronic arsenite stress is impaired, but not completely blocked, in G3BP1/2∆∆ cells. Collectively, our data suggest that SG and PB assembly may facilitate TDP-43 cytoplasmic localization and aggregation but are likely not essential for these events.

Original languageEnglish (US)
Article number1367
Pages (from-to)1-19
Number of pages19
JournalBiomolecules
Volume10
Issue number10
DOIs
StatePublished - Oct 2020

Keywords

  • P-bodies
  • Stress granules
  • TDP-43

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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