Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates

Garnier, Cyrille; Devred, François; Byrne, Deborah; Puppo, Rémy; Roman, Andrei; Malesinski, Soazig; Golovin, Andrey V.; Lebrun, Régine; Ninkina, Natalia; Tsvetkov, Philipp O.

doi:10.1038/s41598-017-07215-7

Cited by 53 publications

(71 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Zinc, which plays an important role in many physiological processes, has been implicated in the molecular mechanisms of many NDs by favoring aggregation of proteins such as amyloid beta, FUS, TDP-43 [21,30]. Recent in vitro studies showed that zinc could also impact Tau aggregation into PHF, a hallmark of several tauopathies.…”

Section: Discussionmentioning

confidence: 99%

“…Four microliters of incubated Tau samples (30 μM) was placed on carbon-coated copper grids (300 mesh) for 1 min. After blotting, grids were washed with distilled water and blotted again, and negatively stained for 30 s with 2% (wt/vol) uranyl acetate as previously described [21]. The grids were then dried and observed with a JEOL 2200FS transmission electron microscope (Tokyo, Japan) operating at 200 kV.…”

Section: Transmission Electron Microscopymentioning

confidence: 99%

“…Interestingly, zinc ions were found to play a critical role in the development of several different NDs including AD and PD. Zinc can bind not only to a number of prone-toaggregate proteins implicated in neurodegeneration (such as amyloid-β [17], FUS/TLS [18], α-synuclein [19], TDP-43 [20,21], etc.) and favor their aggregation, but also induce aggregation of stable proteins [22].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau

Roman

Devred

Byrne

et al. 2019

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

Tau is an intrinsically disordered microtubule-associated protein that is implicated in several neurodegenerative disorders called tauopathies. In these diseases, Tau is found in the form of intracellular inclusions that consist of aggregated paired helical filaments (PHFs) in neurons. Given the importance of this irreversible PHF formation in neurodegenerative disease, Tau aggregation has been extensively studied. Several different factors, such as mutations or post translational modifications, have been shown to influence the formation of late-stage non-reversible Tau aggregates. It was recently shown that zinc ions accelerated heparin-induced oligomerization of Tau constructs. Indeed, in vitro studies of PHFs have usually been performed in the presence of additional co-factors, such as heparin, in order to accelerate their formation. Using turbidimetry, we investigated the impact of zinc ions on Tau in the absence of heparin and found that zinc is able to induce a temperature-dependent reversible oligomerization of Tau. The obtained oligomers were not amyloid-like and dissociated instantly following zinc chelation or a temperature decrease. Finally, a combination of isothermal titration calorimetry and dynamic light scattering experiments showed zinc binding to a high-affinity binding site and three low-affinity sites on Tau, accompanied by a change in Tau folding. Altogether, our findings stress the importance of zinc in Tau oligomerization. This newly identified Zn-induced oligomerization mechanism may be a part of a pathway different of and concurrent to Tau aggregation cascade leading to PHF formation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Transmission Electron Microscopymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau

Roman

Devred

Byrne

et al. 2019

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The thermostability of MAPK14 was measured in the presence of different concentrations of MBZ in 50 mM HEPES buffer in the presence of 200 mM NaCl and 2% DMSO at pH 7.5 using a label-free fluorimetric analysis with a Prometheus NT.Plex instrument (NanoTemper Technologies), as described previously [52]. NanoDSF grade capillaries were filled with a 10 µM solution of interest.…”

Section: Nano Differential Scanning Fluorimetry Assaymentioning

confidence: 99%

In silicomolecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

Ariey-Bonnet

Carrasco

Grand

et al. 2020

Preprint

View full text Add to dashboard Cite

The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already-approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cells in vitro. Our in silico approach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly up-regulated at the gene level in glioblastoma as compared to normal brain tissue. Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2 and MAPK14/p38α. Mebendazole could inhibit the activity of these kinases in vitro in a dose-dependent manner, with a high potency against MAPK14. Its direct binding to MAPK14 was further validated in vitro and inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases. Significance StatementThis study provides a framework to investigate drug polypharmacology by rapidly identifying novel molecular targets of already-approved drugs. It unveils a new mechanism involved in the anticancer activity of anti-helminthic drug, mebendazole, which is currently being repurposed for the treatment of brain tumors. By helping to decipher the mechanism(s) of action of repurposed drugs in their new indications, this approach could contribute to the development of safer and more effective therapeutic strategies in oncology and beyond.

show abstract

“…12:301. doi: 10.3389/fnmol.2019.00301 In the original article, there was an error. In "Binding of Zinc was shown to increase TDP-43 thermostability and formed Thioflavin-T-positive aggregates, reminiscent of amyloid nuclei (Garnier et al, 2017)." The word "increase" should be replaced by "decrease".…”

Section: A Corrigendum Onmentioning

confidence: 99%