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 G3BP1/2ΔΔ 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.
Highlights
Amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease is a progressive neurodegenerative disease characterized by the death of upper and lower motor neurons, resulting in death, typically around 2–5 years after diagnosis
A reasonable speculation based on prior mammalian work is that TAR DNA-binding protein 43 (TDP-43) s RNA-binding activity and intrinsically disordered (IDR) C-terminus confer a high valency potential to interact with other SG components and enhance existing yeast SG assembly mechanisms
A strong block (G3BP1/2∆∆) to SG assembly in mammalian cells completely impairs the formation of cytoplasmic TDP-43 foci under acute high arsenite stress (Figure 5) and reduces formation of TDP-43 cytoplasmic foci during and following a low arsenite chronic stress (Figure 5)
Summary
Amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease is a progressive neurodegenerative disease characterized by the death of upper and lower motor neurons, resulting in death, typically around 2–5 years after diagnosis. 90% and 10% of cases are sporadic and familial, respectively [1]. While the mutations associated with both the sporadic and familial forms of the disease can be varied, aggregates of hyperphosphorylated, ubiquitinated and truncated TAR DNA-binding protein 43 (TDP-43) within patients’ motor neurons and glial cells is a common feature in 97% of ALS cases [1,2,3]. Numerous studies indicate that TDP-43 aggregates may reflect both a loss and toxic gain of function, the relative contributions of both to ALS disease remain contentious [5]. Various studies that have targeted clearance of cytoplasmic TDP-43 have resulted in a mitigation of TDP-43 aggregation and toxicity [6,7], suggesting that prevention of TDP-43 mislocalization and aggregation in the cytoplasm may be a promising avenue of therapeutic research
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