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  Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology

Huang, Y., Wen, J., Ramirez, L.-M., Gümüşdil, E., Pokhrel, P., Man, V. H., et al. (2023). Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology. Nature Communications, 14: 5444. doi:10.1038/s41467-023-41241-6.

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 Creators:
Huang, Yongqi, Author
Wen, Jitao, Author
Ramirez, Lisa-Marie, Author
Gümüşdil, Eymen, Author
Pokhrel, Pravin, Author
Man, Viet H., Author
Ye, Haiqiong, Author
Han, Yue, Author
Liu, Yunfei, Author
Li, Ping, Author
Su, Zhengding, Author
Wang, Junmei, Author
Mao, Hanbin, Author
Zweckstetter, Markus1, 2, Author           
Perrett, Sarah, Author
Wu, Si, Author
Gao, Meng, Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350128              
2Department of NMR Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350124              

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 Abstract: Preventing tau aggregation is a potential therapeutic strategy in Alzheimer’s disease and other tauopathies. Recently, liquid–liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid–liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.

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Language(s): eng - English
 Dates: 2023-09-06
 Publication Status: Published online
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-023-41241-6
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Project name : This work was supported by National Natural Science Foundation of China (#32000883 to M.G., #31920103011 to S.P., and #32171443 to S.W.), China Postdoctoral Science Foundation (#2022TQ0357 to J.W.), the CAS Center of Excellence in Biomacromolecules (S.P.), Hubei University of Technology (Y. Huang, M.G., and Z.S.). M.Z. was supported by the European Research Council (ERC) under the EU Horizon 2020 research and innovation program (grant agreement No. 787679). Y. Huang thanks Zhe Hu (Huazhong Agricultural University) for his help with the FRAP experiments and Chengdong Huang (University of Science and Technology of China) for sharing a plasmid encoding 2N4R tau. L.-M.R., E.G., and M.Z. thank Maria-Sol Cima-Omori for preparation of 15N-labeled tau.
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Project name : -
Grant ID : 787679
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 14 Sequence Number: 5444 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723