Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation

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

doi:10.3390/biom10101367

Cited by 31 publications

(26 citation statements)

References 68 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since then, TDP-43 has been extensively studied relative to the formation of SGs as agents underlying pathological inclusions of the TDP-43 protein in the cytoplasm and nucleus. However, recent data point to a rather indirect relationship between the assembly of SGs and cytoplasmic aggregation of TDP-43 [ 47 , 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…TDP-43 has been linked to the formation and regulation of mRNPs arising under stress conditions, namely stress granules [ 44 , 45 , 46 ]. Recent findings suggest that the occurrence of cytoplasmic TDP-43 inclusions is complex, and SGs may facilitate, but are not required for, the aggregation of TDP-43 in the cytoplasm [ 47 , 48 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

eIF3a Destabilization and TDP-43 Alter Dynamics of Heat-Induced Stress Granules

Malcová

Senohrábková

Nováková

et al. 2021

IJMS

View full text Add to dashboard Cite

Stress granules (SGs) are membrane-less assemblies arising upon various stresses in eukaryotic cells. They sequester mRNAs and proteins from stressful conditions and modulate gene expression to enable cells to resume translation and growth after stress relief. SGs containing the translation initiation factor eIF3a/Rpg1 arise in yeast cells upon robust heat shock (HS) at 46 °C only. We demonstrate that the destabilization of Rpg1 within the PCI domain in the Rpg1-3 variant leads to SGs assembly already at moderate HS at 42 °C. These are bona fide SGs arising upon translation arrest containing mRNAs, which are components of the translation machinery, and associating with P-bodies. HS SGs associate with endoplasmatic reticulum and mitochondria and their contact sites ERMES. Although Rpg1-3-labeled SGs arise at a lower temperature, their disassembly is delayed after HS at 46 °C. Remarkably, the delayed disassembly of HS SGs after the robust HS is reversed by TDP-43, which is a human protein connected with amyotrophic lateral sclerosis. TDP-43 colocalizes with HS SGs in yeast cells and facilitates cell regrowth after the stress relief. Based on our results, we propose yeast HS SGs labeled by Rpg1 and its variants as a novel model system to study functions of TDP-43 in stress granules disassembly.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

eIF3a Destabilization and TDP-43 Alter Dynamics of Heat-Induced Stress Granules

Malcová

Senohrábková

Nováková

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…What is less clear at present, is whether this is linked to the formation of classic SGs, and potentially their persistence beyond the short term, or whether it is actually associated with the stress driven phase separation of non-RNA bound TDP-43, that explicitly does not get recruited to SGs. A recent study has demonstrated that impairment of SG assembly impairs the formation of TDP-43 foci in both acute and chronic stress paradigms, but crucially, did not completely prevent their formation, particularly in the chronic model, suggesting that while SGs may facilitate TDP-43 aggregation, TDP-43 proteinopathy can still develop through a SG-independent mechanism [105,110].…”

Section: Cell Typementioning

confidence: 99%

Mechanisms of TDP-43 Proteinopathy Onset and Propagation

Chen

Mitchell

2021

IJMS

View full text Add to dashboard Cite

TDP-43 is an RNA-binding protein that has been robustly linked to the pathogenesis of a number of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. While mutations in the TARDBP gene that codes for the protein have been identified as causing disease in a small subset of patients, TDP-43 proteinopathy is present in the majority of cases regardless of mutation status. This raises key questions regarding the mechanisms by which TDP-43 proteinopathy arises and spreads throughout the central nervous system. Numerous studies have explored the role of a variety of cellular functions on the disease process, and nucleocytoplasmic transport, protein homeostasis, RNA interactions and cellular stress have all risen to the forefront as possible contributors to the initiation of TDP-43 pathogenesis. There is also a small but growing body of evidence suggesting that aggregation-prone TDP-43 can recruit physiological TDP-43, and be transmitted intercellularly, providing a mechanism whereby small-scale proteinopathy spreads from cell to cell, reflecting the spread of clinical symptoms observed in patients. This review will discuss the potential role of the aforementioned cellular functions in TDP-43 pathogenesis, and explore how aberrant pathology may spread, and result in a feed-forward cascade effect, leading to robust TDP-43 proteinopathy and disease.

show abstract

“…TDP-43 and FUS, however, are both RBPs containing prionlike domains as well as other shared domains. Like FUS, TDP-43 has been shown to colocalize with stress granules and p-bodies in yeast 36,70 which is interesting considering that TAF15 had no effect on TDP-43 toxicity. In this regard, it is notable that using the same Y2H assay, we could detect interaction of TAF15 with FUS but not with TDP-43 (data not sown).…”

Section: Discussionmentioning

confidence: 95%

RNA Binding Protein TAF15 Suppresses Toxicity in a Yeast Model of FUS Proteinopathy

Hayden

Kebe

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

Mutations in Fused in Sarcoma (FUS), an RNA binding protein that functions in multiple steps in gene expression regulation and RNA processing, are known to cause familial amyotrophic lateral sclerosis (ALS). Since this discovery, mutations in several other RNA binding proteins (RBPs) have also been linked to ALS. Some of these ALS-associated RBPs have been shown to colocalize with ribonucleoprotein (RNP) granules such as stress granules and processing bodies (p-bodies). Characterization of ALS-associated proteins, their mis-localization, aggregation and toxicity in cellular and animal models have provided critical insights in disease. More and more evidence has emerged supporting a hypothesis that impaired clearance, inappropriate assembly, and dysregulation of RNP granules play a role in ALS. Through genome-scale overexpression screening of a yeast model of FUS toxicity, we found that TAF15, a human RBP with a similar protein domain structure and belonging to the same FET protein family as FUS, suppresses FUS toxicity. The suppressor effect of TAF15 is specific to FUS and not found in other yeast models of neurodegenerative disease-associated proteins. We showed that the RNA recognition motif (RRM) of TAF15 is required for its rescue of FUS toxicity. Furthermore, FUS and TAF15 physically interact, and the C-terminus of TAF15 is required for both the physical protein-protein interaction and its protection against FUS toxicity. Finally, while FUS induces and colocalizes with both stress granules and p-bodies, TAF15 only induces and colocalizes with p-bodies. Importantly, co-expression of FUS and TAF15 induces more p-bodies than individually expressing each gene alone, and FUS toxicity is exacerbated in yeast that is deficient in p-body formation. Overall, our findings suggest a role of p-body formation in the suppression of FUS toxicity by TAF15.

show abstract

Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation

Cited by 31 publications

References 68 publications

eIF3a Destabilization and TDP-43 Alter Dynamics of Heat-Induced Stress Granules

eIF3a Destabilization and TDP-43 Alter Dynamics of Heat-Induced Stress Granules

Mechanisms of TDP-43 Proteinopathy Onset and Propagation

RNA Binding Protein TAF15 Suppresses Toxicity in a Yeast Model of FUS Proteinopathy

Contact Info

Product

Resources

About